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Mechanisms of autophagy–lysosome dysfunction in neurodegenerative diseases

Nature Reviews Molecular Cell Biology (2024)Cite this article

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Abstract

Autophagy is a lysosome-based degradative process used to recycle obsolete cellular constituents and eliminate damaged organelles and aggregate-prone proteins. Their postmitotic nature and extremely polarized morphologies make neurons particularly vulnerable to disruptions caused by autophagy–lysosomal defects, especially as the brain ages. Consequently, mutations in genes regulating autophagy and lysosomal functions cause a wide range of neurodegenerative diseases. Here, we review the role of autophagy and lysosomes in neurodegenerative diseases such as Alzheimer disease, Parkinson disease and frontotemporal dementia. We also consider the strong impact of cellular ageing on lysosomes and autophagy as a tipping point for the late-age emergence of related neurodegenerative disorders. Many of these diseases have primary defects in autophagy, for example affecting autophagosome formation, and in lysosomal functions, especially pH regulation and calcium homeostasis. We have aimed to provide an integrative framework for understanding the central importance of autophagic–lysosomal function in neuronal health and disease.

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Fig. 1: Autophagy–lysosomal pathway in neurons.
Fig. 2: Causal genes for adult-onset neurodegenerative disease commonly disrupt autophagic–lysosomal function.
Fig. 3: v-ATPase and lysosome acidification in adult neurodegenerative disease.
Fig. 4: Lysosomal ion imbalances in neurodegenerative disease.
Fig. 5: Pathological consequences of chronic lysosomal dysfunction.
Fig. 6: Evolution of autophagy–lysosome dysfunction in Alzheimer disease leading to neurodegeneration.

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References

  1. Ross, C. A. & Poirier, M. A. Protein aggregation and neurodegenerative disease. Nat. Med. 10 Suppl, S10–S17 (2004).

    Article  PubMed  Google Scholar 

  2. Jayaraj, G. G., Hipp, M. S. & Hartl, F. U. Functional modules of the proteostasis network. Cold Spring Harb. Perspect. Biol. 12, 30833457 (2020).

    Article  Google Scholar 

  3. Nishida, Y. et al. Discovery of Atg5/Atg7-independent alternative macroautophagy. Nature 461, 654–658 (2009).

    Article  CAS  PubMed  Google Scholar 

  4. Fleming, A. et al. The different autophagy degradation pathways and neurodegeneration. Neuron 110, 935–966 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Bourdenx, M. et al. Chaperone-mediated autophagy prevents collapse of the neuronal metastable proteome. Cell 184, 2696–2714.e25 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Liu, G. Y. & Sabatini, D. M. mTOR at the nexus of nutrition, growth, ageing and disease. Nat. Rev. Mol. Cell Biol. 21, 183–203 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Settembre, C. & Perera, R. M. Lysosomes as coordinators of cellular catabolism, metabolic signalling and organ physiology. Nat. Rev. Mol. Cell Biol. 25, 223–245 (2024).

    Article  CAS  PubMed  Google Scholar 

  8. Son, S. M. et al. Leucine signals to mTORC1 via its metabolite acetyl-coenzyme A. Cell Metab. 29, 192–201.e7 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Son, S. M. et al. Leucine regulates autophagy via acetylation of the mTORC1 component raptor. Nat. Commun. 11, 3148 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Korolchuk, V. I. et al. Lysosomal positioning coordinates cellular nutrient responses. Nat. Cell Biol. 13, 453–460 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Ding, W. X. et al. Oncogenic transformation confers a selective susceptibility to the combined suppression of the proteasome and autophagy. Mol. Cancer Ther. 8, 2036–2045 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Korolchuk, V. I., Mansilla, A., Menzies, F. M. & Rubinsztein, D. C. Autophagy inhibition compromises degradation of ubiquitin–proteasome pathway substrates. Mol. Cell 33, 517–527 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Ballabio, A. & Bonifacino, J. S. Lysosomes as dynamic regulators of cell and organismal homeostasis. Nat. Rev. Mol. Cell Biol. 21, 101–118 (2020).

    Article  CAS  PubMed  Google Scholar 

  14. Ravikumar, B., Moreau, K., Jahreiss, L., Puri, C. & Rubinsztein, D. C. Plasma membrane contributes to the formation of pre-autophagosomal structures. Nat. Cell Biol. 12, 747–757 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Fraser, J. et al. Targeting of early endosomes by autophagy facilitates EGFR recycling and signalling. EMBO Rep. 20, e47734 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Lees, M. B. Basic Neurochemistry 5th edn, Vol. 39 (Raven Press, 1994).

  17. Lee, S., Sato, Y. & Nixon, R. A. Lysosomal proteolysis inhibition selectively disrupts axonal transport of degradative organelles and causes an Alzheimer’s-like axonal dystrophy. J. Neurosci. 31, 7817–7830 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Lie, P. P. Y. et al. Post-Golgi carriers, not lysosomes, confer lysosomal properties to pre-degradative organelles in normal and dystrophic axons. Cell Rep. 35, 109034 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Lie, P. P. Y. et al. Axonal transport of late endosomes and amphisomes is selectively modulated by local Ca2+ efflux and disrupted by PSEN1 loss of function. Sci. Adv. 8, eabj5716 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Overly, C. C. & Hollenbeck, P. J. Dynamic organization of endocytic pathways in axons of cultured sympathetic neurons. J. Neurosci. 16, 6056–6064 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Yap, C. C., Mason, A. J. & Winckler, B. Dynamics and distribution of endosomes and lysosomes in dendrites. Curr. Opin. Neurobiol. 74, 102537 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Lipka, J., Kuijpers, M., Jaworski, J. & Hoogenraad, C. C. Mutations in cytoplasmic dynein and its regulators cause malformations of cortical development and neurodegenerative diseases. Biochem. Soc. Trans. 41, 1605–1612 (2013).

    Article  CAS  PubMed  Google Scholar 

  23. Aranda-Anzaldo, A. The post-mitotic state in neurons correlates with a stable nuclear higher-order structure. Commun. Integr. Biol. 5, 134–139 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Plascencia-Villa, G. & Perry, G. Roles of oxidative stress in synaptic dysfunction and neuronal cell death in Alzheimer’s disease. Antioxid 12, 1628 (2023).

    Article  CAS  Google Scholar 

  25. Park, S. J. et al. Vinexin contributes to autophagic decline in brain ageing across species. Cell Death Differ. 29, 1055–1070 (2022).

    Article  CAS  PubMed  Google Scholar 

  26. Tsong, H., Holzbaur, E. L. & Stavoe, A. K. Aging differentially affects axonal autophagosome formation and maturation. Autophagy 19, 3079–3095 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Carmona-Gutierrez, D., Hughes, A. L., Madeo, F. & Ruckenstuhl, C. The crucial impact of lysosomes in aging and longevity. Ageing Res. Rev. 32, 2–12 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Hansen, M., Rubinsztein, D. C. & Walker, D. W. Autophagy as a promoter of longevity: insights from model organisms. Nat. Rev. Mol. Cell Biol. 19, 579–593 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Burrinha, T. et al. Deacidification of endolysosomes by neuronal aging drives synapse loss. Traffic 24, 334–354 (2023).

    Article  CAS  PubMed  Google Scholar 

  30. Nixon, R. A. The aging lysosome: an essential catalyst for late-onset neurodegenerative diseases. Biochim. Biophys. Acta Proteins Proteom. 1868, 140443 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Ashkenazi, A. et al. Polyglutamine tracts regulate beclin 1-dependent autophagy. Nature 545, 108–111 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Winslow, A. R. et al. α-Synuclein impairs macroautophagy: implications for Parkinson’s disease. J. Cell Biol. 190, 1023–1037 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Festa, B. P. et al. Microglial-to-neuronal CCR5 signaling regulates autophagy in neurodegeneration. Neuron 111, 2021–2037.e12 (2023).

    Article  CAS  PubMed  Google Scholar 

  34. Plascencia-Villa, G. & Perry, G. Exploring molecular targets for mitochondrial therapies in neurodegenerative diseases. Int. J. Mol. Sci. 24, 12486 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Reed, T. T. et al. Proteomic identification of nitrated brain proteins in early Alzheimer’s disease inferior parietal lobule. J. Cell Mol. Med. 13, 2019–2029 (2009).

    Article  PubMed  Google Scholar 

  36. Di Domenico, F. et al. Impairment of proteostasis network in Down syndrome prior to the development of Alzheimer’s disease neuropathology: redox proteomics analysis of human brain. Biochim. Biophys. Acta 1832, 1249–1259 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  37. Perluigi, M. et al. Redox proteomics in aging rat brain: involvement of mitochondrial reduced glutathione status and mitochondrial protein oxidation in the aging process. J. Neurosci. Res. 88, 3498–3507 (2010).

    Article  CAS  PubMed  Google Scholar 

  38. Butterfield, D. A. Oxidative stress in brain in amnestic mild cognitive impairment. Antioxidants 12, 462 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Klein, M. & Hermey, G. Converging links between adult-onset neurodegenerative Alzheimer’s disease and early life neurodegenerative neuronal ceroid lipofuscinosis? Neural Regen. Res. 18, 1463–1471 (2023).

    Article  CAS  PubMed  Google Scholar 

  40. Simon, M. J., Logan, T., DeVos, S. L. & Di Paolo, G. Lysosomal functions of progranulin and implications for treatment of frontotemporal dementia. Trends Cell Biol. 33, 324–339 (2023).

    Article  CAS  PubMed  Google Scholar 

  41. Hara, T. et al. Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 441, 885–889 (2006).

    Article  CAS  PubMed  Google Scholar 

  42. Komatsu, M. et al. Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 441, 880–884 (2006).

    Article  CAS  PubMed  Google Scholar 

  43. Kim, M. et al. Mutation in ATG5 reduces autophagy and leads to ataxia with developmental delay. eLife 5, e12245 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  44. Jelani, M. et al. A mutation in the major autophagy gene, WIPI2, associated with global developmental abnormalities. Brain 142, 1242–1254 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  45. Collier, J. J. et al. Developmental consequences of defective ATG7-mediated autophagy in humans. N. Engl. J. Med. 384, 2406–2417 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Dooley, H. C. et al. WIPI2 links LC3 conjugation with PI3P, autophagosome formation, and pathogen clearance by recruiting Atg12-5–16L1. Mol. Cell. 55, 238–252 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Kuma, A. et al. The role of autophagy during the early neonatal starvation period. Nature 432, 1032–1036 (2004).

    Article  CAS  PubMed  Google Scholar 

  48. Takahashi, Y. et al. An autophagy assay reveals the ESCRT-III component CHMP2A as a regulator of phagophore closure. Nat. Commun. 9, 2855 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  49. Migliano, S. M., Wenzel, E. M. & Stenmark, H. Biophysical and molecular mechanisms of ESCRT functions, and their implications for disease. Curr. Opin. Cell Biol. 75, 102062 (2022).

    Article  CAS  PubMed  Google Scholar 

  50. Radulovic, M. et al. ESCRT-mediated lysosome repair precedes lysophagy and promotes cell survival. Embo J. 37, e99753 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  51. Eriksson, I., Wäster, P. & Öllinger, K. Restoration of lysosomal function after damage is accompanied by recycling of lysosomal membrane proteins. Cell Death Dis. 11, 370 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Bonet-Ponce, L. et al. LRRK2 mediates tubulation and vesicle sorting from lysosomes. Sci. Adv. 6, eabb2454 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Herbst, S. et al. LRRK2 activation controls the repair of damaged endomembranes in macrophages. EMBO J. 39, e104494 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Morrison, R. et al. LRRK2 kinase dependent and independent function on endolysosomal repair promotes macrophage cell death. Preprint at bioRxiv https://doi.org/10.1101/2023.09.27.559807 (2023).

  55. Chen, J. J. et al. Compromised function of the ESCRT pathway promotes endolysosomal escape of tau seeds and propagation of tau aggregation. J. Biol. Chem. 294, 18952–18966 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Puri, C., Gratian, M. J. & Rubinsztein, D. C. Mammalian autophagosomes form from finger-like phagophores. Dev. Cell. 58 2746–2760.e5 (2023).

    Article  CAS  PubMed  Google Scholar 

  57. Puri, C. et al. A DNM2 centronuclear myopathy mutation reveals a link between recycling endosome scission and autophagy. Dev. Cell 53, 154–168.e6 (2020).

    Article  CAS  PubMed  Google Scholar 

  58. Ravikumar, B. et al. Dynein mutations impair autophagic clearance of aggregate-prone proteins. Nat. Genet. 37, 771–776 (2005).

    Article  CAS  PubMed  Google Scholar 

  59. Ishikawa, K. I. et al. p150glued deficiency impairs effective fusion between autophagosomes and lysosomes due to their redistribution to the cell periphery. Neurosci. Lett. 690, 181–187 (2019).

    Article  CAS  PubMed  Google Scholar 

  60. Cierny, M. et al. Novel destabilizing dynactin variant (DCTN1 p.Tyr78His) in patient with Perry syndrome. Parkinsonism Relat. Disord. 77, 110–113 (2020).

    Article  PubMed  Google Scholar 

  61. Cóppola-Segovia, V. & Reggiori, F. Molecular insights into aggrephagy: their cellular functions in the context of neurodegenerative diseases. J. Mol. Biol. 436, 168493 (2024).

    Article  PubMed  Google Scholar 

  62. D’Arcy, M. S. Mitophagy in health and disease. Molecular mechanisms, regulatory pathways, and therapeutic implications. Apoptosis https://doi.org/10.1007/s10495-024-01977-y (2024).

  63. Iavarone, F., Di Lorenzo, G. & Settembre, C. Regulatory events controlling ER-phagy. Curr. Opin. Cell Biol. 76, 102084 (2022).

    Article  CAS  PubMed  Google Scholar 

  64. Deng, Z. et al. ALS-FTLD-linked mutations of SQSTM1/p62 disrupt selective autophagy and NFE2L2/NRF2 anti-oxidative stress pathway. Autophagy 16, 917–931 (2020).

    Article  CAS  PubMed  Google Scholar 

  65. Lazarou, M. et al. The ubiquitin kinase PINK1 recruits autophagy receptors to induce mitophagy. Nature 524, 309–314 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Khaminets, A. et al. Regulation of endoplasmic reticulum turnover by selective autophagy. Nature 522, 354–358 (2015).

    Article  CAS  PubMed  Google Scholar 

  67. Foronda, H. et al. Heteromeric clusters of ubiquitinated ER-shaping proteins drive ER-phagy. Nature 618, 402–410 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Pickrell, A. M. & Youle, R. J. The roles of PINK1, parkin, and mitochondrial fidelity in Parkinson’s disease. Neuron 85, 257–273 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. McWilliams, T. G. et al. Basal mitophagy occurs independently of PINK1 in mouse tissues of high metabolic demand. Cell Metab. 27, 439–449.e5 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Pirooznia, S. K. et al. PARIS induced defects in mitochondrial biogenesis drive dopamine neuron loss under conditions of parkin or PINK1 deficiency. Mol. Neurodegener. 15, 17 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Goldsmith, J., Ordureau, A., Harper, J. W. & Holzbaur, E. L. F. Brain-derived autophagosome profiling reveals the engulfment of nucleoid-enriched mitochondrial fragments by basal autophagy in neurons. Neuron 110, 967–976.e8 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. D’Acunzo, P. et al. Mitovesicles are a novel population of extracellular vesicles of mitochondrial origin altered in Down syndrome. Sci. Adv. 7, eabe5085 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  73. Hosokawa, N. et al. Nutrient-dependent mTORC1 association with the ULK1–Atg13–FIP200 complex required for autophagy. Mol. Biol. Cell 20, 1981–1991 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Pena-Llopis, S. et al. Regulation of TFEB and v-ATPases by mTORC1. EMBO J. 30, 3242–3258 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Martinez-Vicente, M. et al. Cargo recognition failure is responsible for inefficient autophagy in Huntington’s disease. Nat. Neurosci. 13, 567–576 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Wong, Y. C. & Holzbaur, E. L. The regulation of autophagosome dynamics by huntingtin and HAP1 is disrupted by expression of mutant huntingtin, leading to defective cargo degradation. J. Neurosci. 34, 1293–1305 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Moreau, K. et al. PICALM modulates autophagy activity and tau accumulation. Nat. Commun. 5, 4998 (2014).

    Article  CAS  PubMed  Google Scholar 

  78. Moreau, K., Ravikumar, B., Renna, M., Puri, C. & Rubinsztein, D. C. Autophagosome precursor maturation requires homotypic fusion. Cell 146, 303–317 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Puri, C., Renna, M., Bento, C. F., Moreau, K. & Rubinsztein, D. C. Diverse autophagosome membrane sources coalesce in recycling endosomes. Cell 154, 1285–1299 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Simons, M., Levin, J. & Dichgans, M. Tipping points in neurodegeneration. Neuron 111, 2954–2968 (2023).

    Article  CAS  PubMed  Google Scholar 

  81. Sarkar, S. et al. Complex inhibitory effects of nitric oxide on autophagy. Mol. Cell. 43, 19–32 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Ping, S., Qiu, X., Kyle, M. & Zhao, L. R. Brain-derived CCR5 contributes to neuroprotection and brain repair after experimental stroke. Aging Dis. 12, 72–92 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  83. Choi, I. et al. Autophagy enables microglia to engage amyloid plaques and prevents microglial senescence. Nat. Cell Biol. 25, 963–974 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Wang, C., Telpoukhovskaia, M. A., Bahr, B. A., Chen, X. & Gan, L. Endo-lysosomal dysfunction: a converging mechanism in neurodegenerative diseases. Curr. Opin. Neurobiol. 48, 52–58 (2018).

    Article  CAS  PubMed  Google Scholar 

  85. Nixon, R. A. The role of autophagy in neurodegenerative disease. Nat. Med. 19, 983–997 (2013).

    Article  CAS  PubMed  Google Scholar 

  86. de Duve, C. The lysosome turns fifty. Nat. Cell Biol. 7, 847–849 (2005).

    Article  PubMed  Google Scholar 

  87. de Duve, C. Lysosomes, a New Group of Cytoplasmic Particle (Ronald Press, 1959).

  88. Nixon, R. A., Yang, D. S. & Lee, J. H. Neurodegenerative lysosomal disorders: a continuum from development to late age. Autophagy 4, 590–599 (2008).

    Article  CAS  PubMed  Google Scholar 

  89. Ponsford, A. H. et al. Live imaging of intra-lysosome pH in cell lines and primary neuronal culture using a novel genetically encoded biosensor. Autophagy 17, 1500–1518 (2021).

    Article  CAS  PubMed  Google Scholar 

  90. Yoshimori, T., Yamamoto, A., Moriyama, Y., Futai, M. & Tashiro, Y. Bafilomycin A1, a specific inhibitor of vacuolar-type H+-ATPase, inhibits acidification and protein degradation in lysosomes of cultured cells. J. Biol. Chem. 266, 17707–17712 (1991).

    Article  CAS  PubMed  Google Scholar 

  91. Stoka, V., Turk, V. & Turk, B. Lysosomal cathepsins and their regulation in aging and neurodegeneration. Ageing Res. Rev. 32, 22–37 (2016).

    Article  CAS  PubMed  Google Scholar 

  92. Nishi, T. & Forgac, M. The vacuolar (H+)-ATPases-nature’s most versatile proton pumps. Nat. Rev. Mol. Cell Biol. 3, 94–103 (2002).

    Article  CAS  PubMed  Google Scholar 

  93. Collins, M. P. & Forgac, M. Regulation and function of v-ATPases in physiology and disease. Biochim. Biophys. Acta Biomembr. 1862, 183341 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Coffey, E. E., Beckel, J. M., Laties, A. M. & Mitchell, C. H. Lysosomal alkalization and dysfunction in human fibroblasts with the Alzheimer’s disease-linked presenilin 1 A246E mutation can be reversed with cAMP. Neuroscience 263, 111–124 (2014).

    Article  CAS  PubMed  Google Scholar 

  95. Colacurcio, D. J. & Nixon, R. A. Disorders of lysosomal acidification-the emerging role of v-ATPase in aging and neurodegenerative disease. Ageing Res. Rev. 32, 75–88 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Zhang, J. et al. Lysosomal LAMP proteins regulate lysosomal pH by direct inhibition of the TMEM175 channel. Mol. Cell 83, 2524–2539.e7 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Turk, B. et al. Acidic pH as a physiological regulator of human cathepsin L activity. Eur. J. Biochem. 259, 926–932 (1999).

    Article  CAS  PubMed  Google Scholar 

  98. Lie, P. P. Y. & Nixon, R. A. Lysosome trafficking and signaling in health and neurodegenerative diseases. Neurobiol. Dis. 122, 94–105 (2019).

    Article  CAS  PubMed  Google Scholar 

  99. Zoncu, R. et al. mTORC1 senses lysosomal amino acids through an inside-out mechanism that requires the vacuolar H+-ATPase. Science 334, 678–683 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Jung, J., Genau, H. M. & Behrends, C. Amino acid-dependent mTORC1 regulation by the lysosomal membrane protein SLC38A9. Mol. Cell Biol. 35, 2479–2494 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Rebsamen, M. et al. SLC38A9 is a component of the lysosomal amino acid sensing machinery that controls mTORC1. Nature 519, 477–481 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Wang, S. et al. Metabolism. Lysosomal amino acid transporter SLC38A9 signals arginine sufficiency to mTORC1. Science 347, 188–194 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Bendl, J. et al. The three-dimensional landscape of cortical chromatin accessibility in Alzheimer’s disease. Nat. Neurosci. 25, 1366–1378 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Lapierre, L. R. et al. The TFEB orthologue HLH-30 regulates autophagy and modulates longevity in Caenorhabditis elegans. Nat. Commun. 4, 2267 (2013).

    Article  PubMed  Google Scholar 

  105. Vilchez, D., Simic, M. S. & Dillin, A. Proteostasis and aging of stem cells. Trends Cell Biol. 24, 161–170 (2014).

    Article  CAS  PubMed  Google Scholar 

  106. El Far, O. & Seagar, M. A role for v-ATPase subunits in synaptic vesicle fusion? J. Neurochem. 117, 603–612 (2011).

    CAS  PubMed  Google Scholar 

  107. Higashida, H., Yokoyama, S., Tsuji, C. & Muramatsu, S. I. Neurotransmitter release: vacuolar ATPase V0 sector c-subunits in possible gene or cell therapies for Parkinson’s, Alzheimer’s, and psychiatric diseases. J. Physiol. Sci. 67, 11–17 (2017).

    Article  CAS  PubMed  Google Scholar 

  108. Lee, J. H. et al. Presenilin 1 maintains lysosomal Ca2+ homeostasis via TRPML1 by regulating vATPase-mediated lysosome acidification. Cell Rep. 12, 1430–1444 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Bourdenx, M. et al. Nanoparticles restore lysosomal acidification defects: Implication for Parkinson and other lysosomal-related diseases. Autophagy 12, 472–483 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Schroder, B. & Saftig, P. Intramembrane proteolysis within lysosomes. Ageing Res. Rev. 32, 51–64 (2016).

    Article  PubMed  Google Scholar 

  111. De Strooper, B., Iwatsubo, T. & Wolfe, M. S. Presenilins and γ-secretase: structure, function, and role in Alzheimer disease. Cold Spring Harb. Perspect. Med. 2, a006304 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  112. Haapasalo, A. & Kovacs, D. M. The many substrates of presenilin/γ-secretase. J. Alzheimers Dis. 25, 3–28 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Sannerud, R. et al. Restricted location of PSEN2/γ-secretase determines substrate specificity and generates an intracellular Aβ pool. Cell 166, 193–208 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Pasternak, S. H. et al. Presenilin-1, nicastrin, amyloid precursor protein, and γ-secretase activity are co-localized in the lysosomal membrane. J. Biol. Chem. 278, 26687–26694 (2003).

    Article  CAS  PubMed  Google Scholar 

  115. Bagshaw, R. D., Pasternak, S. H., Mahuran, D. J. & Callahan, J. W. Nicastrin is a resident lysosomal membrane protein. Biochem. Biophys. Res. Commun. 300, 615–618 (2003).

    Article  CAS  PubMed  Google Scholar 

  116. Yu, W. H. et al. Autophagic vacuoles are enriched in amyloid precursor protein-secretase activities: implications for β-amyloid peptide over-production and localization in Alzheimer’s disease. Int. J. Biochem. Cell Biol. 36, 2531–2540 (2004).

    Article  CAS  PubMed  Google Scholar 

  117. Wolfe, D. M. et al. Autophagy failure in Alzheimer’s disease and the role of defective lysosomal acidification. Eur. J. Neurosci. 37, 1949–1961 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  118. Lee, J. H. et al. Lysosomal proteolysis and autophagy require presenilin 1 and are disrupted by Alzheimer-related PS1 mutations. Cell 141, 1146–1158 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Avrahami, L. et al. Inhibition of glycogen synthase kinase-3 ameliorates β-amyloid pathology and restores lysosomal acidification and mammalian target of rapamycin activity in the Alzheimer disease mouse model: in vivo and in vitro studies. J. Biol. Chem. 288, 1295–1306 (2013).

    Article  CAS  PubMed  Google Scholar 

  120. Sharma, D. et al. γ-Secretase orthologs are required for lysosomal activity and autophagic degradation in Dictyostelium discoideum, independent of PSEN (presenilin) proteolytic function. Autophagy 15, 1407–1418 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Im, E. et al. Lysosomal dysfunction in Down syndrome and Alzheimer mouse models is caused by selective v-ATPase inhibition by Tyr682 phosphorylated APP βCTF. Sci. Adv. 9, eadg1925 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Lee, J. H. et al. Transgenic expression of a ratiometric autophagy probe specifically in neurons enables the interrogation of brain autophagy in vivo. Autophagy 15, 543–557 (2019).

    Article  CAS  PubMed  Google Scholar 

  123. Mustaly-Kalimi, S. et al. Protein mishandling and impaired lysosomal proteolysis generated through calcium dysregulation in Alzheimer’s disease. Proc. Natl Acad. Sci. USA 119, e2211999119 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Malampati, S. et al. Pharmacological reacidification of lysosomes attenuates intraneuronal amyloidosis, early neuron death, and amyloid plaque formation in 5xFAD mice. In Alzheimer’s Association International Conference (2024).

  125. Chou, C. C. et al. Proteostasis and lysosomal quality control deficits in Alzheimer’s disease neurons. Preprint at bioRxiv https://doi.org/10.1101/2023.03.27.534444 (2023).

  126. Yang, M. et al. Alzheimer’s disease presenilin-1 mutation sensitizes neurons to impaired autophagy flux and propofol neurotoxicity: role of calcium dysregulation. J. Alzheimers Dis. 67, 137–147 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Coen, K. et al. Lysosomal calcium homeostasis defects, not proton pump defects, cause endo-lysosomal dysfunction in PSEN-deficient cells. J. Cell Biol. 198, 23–35 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Nixon, R. A., Lee, J. H. & Wolfe, D. Comments on presenilins and lysosome pH revisited again. J. Neurosci. https://doi.org/10.1523/JNEUROSCI.0556-12.2012 (2012).

  129. Tong, B. C. et al. Lysosomal TPCN (two pore segment channel) inhibition ameliorates β-amyloid pathology and mitigates memory impairment in Alzheimer disease. Autophagy 18, 624–642 (2022).

    Article  CAS  PubMed  Google Scholar 

  130. Karagas, N. E. & Venkatachalam, K. Roles for the endoplasmic reticulum in regulation of neuronal calcium homeostasis. Cells 8, 1232 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Lee, J. H. et al. Faulty autolysosome acidification in Alzheimer’s disease mouse models induces autophagic build-up of Aβ in neurons, yielding senile plaques. Nat. Neurosci. 25, 688–701 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Jiang, Y. et al. Lysosomal dysfunction in down syndrome is APP-dependent and mediated by APP-βCTF (C99). J. Neurosci. 39, 5255–5268 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Pulina, M. V., Hopkins, M., Haroutunian, V., Greengard, P. & Bustos, V. C99 selectively accumulates in vulnerable neurons in Alzheimer’s disease. Alzheimers Dement. 16, 273–282 (2020).

    Article  PubMed  Google Scholar 

  134. Nixon, R. A. Amyloid precursor protein and endosomal–lysosomal dysfunction in Alzheimer’s disease: inseparable partners in a multifactorial disease. FASEB J. 31, 2729–2743 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Lauritzen, I. et al. The β-secretase-derived C-terminal fragment of βAPP, C99, but not Aβ, is a key contributor to early intraneuronal lesions in triple-transgenic mouse hippocampus. J. Neurosci. 32, 16243–16255a (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Lauritzen, I. et al. Intraneuronal aggregation of the β-CTF fragment of APP (C99) induces Aβ-independent lysosomal-autophagic pathology. Acta Neuropathol. 132, 257–276 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Tamayev, R., Matsuda, S., Arancio, O. & D’Adamio, L. β- but not γ-secretase proteolysis of APP causes synaptic and memory deficits in a mouse model of dementia. EMBO Mol. Med. 4, 171–179 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Lauritzen, I. et al. Targeting γ-secretase triggers the selective enrichment of oligomeric APP-CTFs in brain extracellular vesicles from Alzheimer cell and mouse models. Transl. Neurodegener. 8, 35 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  139. Jiang, Y. et al. Partial BACE1 reduction in a Down syndrome mouse model blocks Alzheimer-related endosomal anomalies and cholinergic neurodegeneration: role of APP-CTF. Neurobiol. Aging 39, 90–98 (2016).

    Article  CAS  PubMed  Google Scholar 

  140. Jiang, Y. et al. Alzheimer’s-related endosome dysfunction in down syndrome is Aβ-independent but requires APP and is reversed by BACE-1 inhibition. Proc. Natl Acad. Sci. USA 107, 1630–1635 (2010).

    Article  CAS  PubMed  Google Scholar 

  141. Area-Gomez, E. et al. A key role for MAM in mediating mitochondrial dysfunction in Alzheimer disease. Cell Death Dis. 9, 335 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  142. Van Acker, Z. P. et al. Phospholipase D3 degrades mitochondrial DNA to regulate nucleotide signaling and APP metabolism. Nat. Commun. 14, 2847 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  143. Yuan, P. et al. PLD3 affects axonal spheroids and network defects in Alzheimer’s disease. Nature 612, 328–337 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Wallings, R., Connor-Robson, N. & Wade-Martins, R. LRRK2 interacts with the vacuolar-type H+-ATPase pump a1 subunit to regulate lysosomal function. Hum. Mol. Genet. 28, 2696–2710 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Bagh, M. B. et al. Misrouting of v-ATPase subunit V0a1 dysregulates lysosomal acidification in a neurodegenerative lysosomal storage disease model. Nat. Commun. 8, 14612 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  146. Steger, M. et al. Phosphoproteomics reveals that Parkinson’s disease kinase LRRK2 regulates a subset of Rab GTPases. eLife 5, e12813 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  147. Ramirez, A. et al. Hereditary parkinsonism with dementia is caused by mutations in ATP13A2, encoding a lysosomal type 5 P-type ATPase. Nat. Genet. 38, 1184–1191 (2006).

    Article  CAS  PubMed  Google Scholar 

  148. Farias, F. H. et al. A truncating mutation in ATP13A2 is responsible for adult-onset neuronal ceroid lipofuscinosis in Tibetan terriers. Neurobiol. Dis. 42, 468–474 (2011).

    Article  CAS  PubMed  Google Scholar 

  149. Schultheis, P. J. et al. Atp13a2-deficient mice exhibit neuronal ceroid lipofuscinosis, limited α-synuclein accumulation and age-dependent sensorimotor deficits. Hum. Mol. Genet. 22, 2067–2082 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Bras, J., Verloes, A., Schneider, S. A., Mole, S. E. & Guerreiro, R. J. Mutation of the parkinsonism gene ATP13A2 causes neuronal ceroid-lipofuscinosis. Hum. Mol. Genet. 21, 2646–2650 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. van Veen, S. et al. ATP13A2 deficiency disrupts lysosomal polyamine export. Nature 578, 419–424 (2020).

    Article  PubMed  Google Scholar 

  152. van Veen, S. et al. Cellular function and pathological role of ATP13A2 and related P-type transport ATPases in Parkinson’s disease and other neurological disorders. Front. Mol. Neurosci. 7, 48 (2014).

    PubMed  PubMed Central  Google Scholar 

  153. Dubos, A. et al. Conditional depletion of intellectual disability and parkinsonism candidate gene ATP6AP2 in fly and mouse induces cognitive impairment and neurodegeneration. Hum. Mol. Genet. 24, 6736–6755 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Korvatska, O. et al. Altered splicing of ATP6AP2 causes X-linked parkinsonism with spasticity (XPDS). Hum. Mol. Genet. 22, 3259–3268 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Park, J. S. et al. Pathogenic effects of novel mutations in the P-type ATPase ATP13A2 (PARK9) causing Kufor–Rakeb syndrome, a form of early-onset parkinsonism. Hum. Mutat. 32, 956–964 (2011).

    Article  CAS  PubMed  Google Scholar 

  156. Dehay, B. et al. Loss of P-type ATPase ATP13A2/PARK9 function induces general lysosomal deficiency and leads to Parkinson disease neurodegeneration. Proc. Natl Acad. Sci. USA 109, 9611–9616 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Usenovic, M., Tresse, E., Mazzulli, J. R., Taylor, J. P. & Krainc, D. Deficiency of ATP13A2 leads to lysosomal dysfunction, α-synuclein accumulation, and neurotoxicity. J. Neurosci. 32, 4240–4246 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Vrijsen, S., Houdou, M., Cascalho, A., Eggermont, J. & Vangheluwe, P. Polyamines in Parkinson’s disease: balancing between neurotoxicity and neuroprotection. Annu. Rev. Biochem. 92, 435–464 (2023).

    Article  CAS  PubMed  Google Scholar 

  159. Jinn, S. et al. Functionalization of the TMEM175 p.M393T variant as a risk factor for Parkinson disease. Hum. Mol. Genet. 28, 3244–3254 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Krohn, L. et al. Genetic, structural, and functional evidence link TMEM175 to synucleinopathies. Ann. Neurol. 87, 139–153 (2020).

    Article  CAS  PubMed  Google Scholar 

  161. Palomba, N. P. et al. Common and rare variants in TMEM175 gene concur to the pathogenesis of Parkinson’s disease in Italian patients. Mol. Neurobiol. 60, 2150–2173 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Cang, C., Aranda, K., Seo, Y. J., Gasnier, B. & Ren, D. TMEM175 Is an organelle K+ channel regulating lysosomal function. Cell 162, 1101–1112 (2015).

    Article  CAS  PubMed  Google Scholar 

  163. Jinn, S. et al. TMEM175 deficiency impairs lysosomal and mitochondrial function and increases α-synuclein aggregation. Proc. Natl Acad. Sci. USA 114, 2389–2394 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Hu, M. et al. Parkinson’s disease-risk protein TMEM175 is a proton-activated proton channel in lysosomes. Cell 185, 2292–2308.e20 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Zheng, W. et al. pH regulates potassium conductance and drives a constitutive proton current in human TMEM175. Sci. Adv. 8, eabm1568 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Tang, T., Jian, B. & Liu, Z. Transmembrane protein 175, a lysosomal ion channel related to Parkinson’s disease. Biomolecules 13, 802 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Wie, J. et al. A growth-factor-activated lysosomal K+ channel regulates Parkinson’s pathology. Nature 591, 431–437 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Henderson, M. X. et al. Spread of α-synuclein pathology through the brain connectome is modulated by selective vulnerability and predicted by network analysis. Nat. Neurosci. 22, 1248–1257 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Rohrer, J. D. et al. The heritability and genetics of frontotemporal lobar degeneration. Neurology 73, 1451–1456 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Logan, T. et al. Rescue of a lysosomal storage disorder caused by Grn loss of function with a brain penetrant progranulin biologic. Cell 184, 4651–4668.e25 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Hasan, S. et al. Multi-modal proteomic characterization of lysosomal function and proteostasis in progranulin-deficient neurons. Mol. Neurodegener. 18, 87 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Klein, Z. A. et al. Loss of TMEM106B ameliorates lysosomal and frontotemporal dementia-related phenotypes in progranulin-deficient mice. Neuron 95, 281–296.e6 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Brady, O. A., Zheng, Y., Murphy, K., Huang, M. & Hu, F. The frontotemporal lobar degeneration risk factor, TMEM106B, regulates lysosomal morphology and function. Hum. Mol. Genet. 22, 685–695 (2013).

    Article  CAS  PubMed  Google Scholar 

  174. Schwenk, B. M. et al. The FTLD risk factor TMEM106B and MAP6 control dendritic trafficking of lysosomes. EMBO J. 33, 450–467 (2014).

    CAS  PubMed  Google Scholar 

  175. Lang, C. M. et al. Membrane orientation and subcellular localization of transmembrane protein 106B (TMEM106B), a major risk factor for frontotemporal lobar degeneration. J. Biol. Chem. 287, 19355–19365 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Van Deerlin, V. M. et al. Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP-43 inclusions. Nat. Genet. 42, 234-239 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Cruchaga, C. et al. Association of TMEM106B gene polymorphism with age at onset in granulin mutation carriers and plasma granulin protein levels. Arch. Neurol. 68, 581–586 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  178. Finch, N. et al. TMEM106B regulates progranulin levels and the penetrance of FTLD in GRN mutation carriers. Neurology 76, 467–474 (2011).

    Article  CAS  PubMed  Google Scholar 

  179. Feng, T. et al. Loss of TMEM106B and PGRN leads to severe lysosomal abnormalities and neurodegeneration in mice. EMBO Rep. 21, e50219 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Werner, G. et al. Loss of TMEM106B potentiates lysosomal and FTLD-like pathology in progranulin-deficient mice. EMBO Rep. 21, e50241 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Zhou, X. et al. Loss of TMEM106B leads to myelination deficits: implications for frontotemporal dementia treatment strategies. Brain 143, 1905–1919 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  182. Stroobants, S., D’Hooge, R. & Damme, M. Aged Tmem106b knockout mice display gait deficits in coincidence with Purkinje cell loss and only limited signs of non-motor dysfunction. Brain Pathol. 31, 223–238 (2021).

    Article  CAS  PubMed  Google Scholar 

  183. Luningschror, P. et al. The FTLD risk factor TMEM106B regulates the transport of lysosomes at the axon initial segment of motoneurons. Cell Rep. 30, 3506–3519.e6 (2020).

    Article  PubMed  Google Scholar 

  184. Yadati, T., Houben, T., Bitorina, A. & Shiri-Sverdlov, R. The ins and outs of cathepsins: physiological function and role in disease management. Cells 9, 1679 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Vidoni, C., Follo, C., Savino, M., Melone, M. A. & Isidoro, C. The role of cathepsin D in the pathogenesis of human neurodegenerative disorders. Med. Res. Rev. 36, 845–870 (2016).

    Article  CAS  PubMed  Google Scholar 

  186. Zhang, K. Y., Yang, S., Warraich, S. T. & Blair, I. P. Ubiquilin 2: a component of the ubiquitin–proteasome system with an emerging role in neurodegeneration. Int. J. Biochem. Cell Biol. 50, 123–126 (2014).

    Article  CAS  PubMed  Google Scholar 

  187. Wu, J. J. et al. ALS/FTD mutations in UBQLN2 impede autophagy by reducing autophagosome acidification through loss of function. Proc. Natl Acad. Sci. USA 117, 15230–15241 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  188. Şentürk, M. et al. Ubiquilins regulate autophagic flux through mTOR signalling and lysosomal acidification. Nat. Cell Biol. 21, 384–396 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  189. Christensen, K. A., Myers, J. T. & Swanson, J. A. pH-dependent regulation of lysosomal calcium in macrophages. J. Cell Sci. 115, 599–607 (2002).

    Article  CAS  PubMed  Google Scholar 

  190. Churchill, G. C. et al. NAADP mobilizes Ca2+ from reserve granules, lysosome-related organelles, in sea urchin eggs. Cell 111, 703–708 (2002).

    Article  CAS  PubMed  Google Scholar 

  191. Guse, A. H. & Lee, H. C. NAADP: a universal Ca2+ trigger. Sci. Signal. 1, re10 (2008).

    Article  PubMed  Google Scholar 

  192. Feng, X. & Yang, J. Lysosomal calcium in neurodegeneration. Messenger 5, 56–66 (2016).

    Article  PubMed  Google Scholar 

  193. Tedeschi, V. & Secondo, A. Emerging role of lysosomal calcium store as a hub of neuroprotection. Neural Regen. Res. 17, 1259–1260 (2022).

    Article  CAS  PubMed  Google Scholar 

  194. Lloyd-Evans, E. & Waller-Evans, H. Lysosomal Ca2+ homeostasis and signaling in health and disease. Cold Spring Harb. Perspect. Biol. 12, a035311 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Medina, D. L. et al. Lysosomal calcium signalling regulates autophagy through calcineurin and TFEB. Nat. Cell Biol. 17, 288–299 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  196. Berman, E. R., Livni, N., Shapira, E., Merin, S. & Levij, I. S. Congenital corneal clouding with abnormal systemic storage bodies: a new variant of mucolipidosis. J. Pediatr. 84, 519–526 (1974).

    Article  CAS  PubMed  Google Scholar 

  197. Shen, D. et al. Lipid storage disorders block lysosomal trafficking by inhibiting a TRP channel and lysosomal calcium release. Nat. Commun. 3, 731 (2012).

    Article  PubMed  Google Scholar 

  198. Samie, M. A. et al. The tissue-specific expression of TRPML2 (MCOLN-2) gene is influenced by the presence of TRPML1. Pflug. Arch. 459, 79–91 (2009).

    Article  CAS  Google Scholar 

  199. Grimm, C., Hassan, S., Wahl-Schott, C. & Biel, M. Role of TRPML and two-pore channels in endolysosomal cation homeostasis. J. Pharmacol. Exp. Ther. 342, 236–244 (2012).

    Article  CAS  PubMed  Google Scholar 

  200. Guse, A. H. Second messenger signaling: multiple receptors for NAADP. Curr. Biol. 19, R521–R523 (2009).

    Article  CAS  PubMed  Google Scholar 

  201. Xiong, J. & Zhu, M. X. Regulation of lysosomal ion homeostasis by channels and transporters. Sci. China Life Sci. 59, 777–791 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. Cheng, X., Zhang, X., Yu, L. & Xu, H. Calcium signaling in membrane repair. Semin. Cell Dev. Biol. 45, 24–31 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. Morgan, A. J., Platt, F. M., Lloyd-Evans, E. & Galione, A. Molecular mechanisms of endolysosomal Ca2+ signalling in health and disease. Biochem. J. 439, 349–374 (2011).

    Article  CAS  PubMed  Google Scholar 

  204. Patel, S. & Cai, X. Evolution of acidic Ca2+ stores and their resident Ca2+-permeable channels. Cell Calcium 57, 222–230 (2015).

    Article  CAS  PubMed  Google Scholar 

  205. Waller-Evans, H. & Lloyd-Evans, E. Regulation of TRPML1 function. Biochem. Soc. Trans. 43, 442–446 (2015).

    Article  CAS  PubMed  Google Scholar 

  206. Soyombo, A. A. et al. TRP-ML1 regulates lysosomal pH and acidic lysosomal lipid hydrolytic activity. J. Biol. Chem. 281, 7294–7301 (2006).

    Article  CAS  PubMed  Google Scholar 

  207. Zhang, X. et al. MCOLN1 is a ROS sensor in lysosomes that regulates autophagy. Nat. Commun. 7, 12109 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  208. Butterfield, D. A., Di Domenico, F., Swomley, A. M., Head, E. & Perluigi, M. Redox proteomics analysis to decipher the neurobiology of Alzheimer-like neurodegeneration: overlaps in Down’s syndrome and Alzheimer’s disease brain. Biochem. J. 463, 177–189 (2014).

    Article  CAS  PubMed  Google Scholar 

  209. Mundy, D. I., Li, W. P., Luby-Phelps, K. & Anderson, R. G. Caveolin targeting to late endosome/lysosomal membranes is induced by perturbations of lysosomal pH and cholesterol content. Mol. Biol. Cell 23, 864–880 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  210. Ollinger, K. & Brunk, U. T. Cellular injury induced by oxidative stress is mediated through lysosomal damage. Free. Radic. Biol. Med. 19, 565–574 (1995).

    Article  CAS  PubMed  Google Scholar 

  211. Samie, M. et al. A TRP channel in the lysosome regulates large particle phagocytosis via focal exocytosis. Dev. Cell 26, 511–524 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  212. Elbaz-Alon, Y. et al. A dynamic interface between vacuoles and mitochondria in yeast. Dev. Cell 30, 95–102 (2014).

    Article  CAS  PubMed  Google Scholar 

  213. Li, L., Tan, J., Miao, Y., Lei, P. & Zhang, Q. ROS and autophagy: interactions and molecular regulatory mechanisms. Cell Mol. Neurobiol. 35, 615–621 (2015).

    Article  PubMed  Google Scholar 

  214. Potz, B. A., Abid, M. R. & Sellke, F. W. Role of calpain in pathogenesis of human disease processes. J. Nat. Sci. 2, e218 (2016).

    PubMed  PubMed Central  Google Scholar 

  215. Nixon, R. A. The calpains in aging and aging-related diseases. Ageing Res. Rev. 2, 407–418 (2003).

    Article  CAS  PubMed  Google Scholar 

  216. Diepenbroek, M. et al. Overexpression of the calpain-specific inhibitor calpastatin reduces human α-synuclein processing, aggregation and synaptic impairment in [A30P]αSyn transgenic mice. Hum. Mol. Genet. 23, 3975–3989 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  217. Menzies, F. M. et al. Calpain inhibition mediates autophagy-dependent protection against polyglutamine toxicity. Cell Death Differ. 22, 433–444 (2015).

    Article  CAS  PubMed  Google Scholar 

  218. Rao, M. V. et al. Specific calpain inhibition by calpastatin prevents tauopathy and neurodegeneration and restores normal lifespan in tau P301L mice. J. Neurosci. 34, 9222–9234 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  219. Requejo-Aguilar, R. Cdk5 and aberrant cell cycle activation at the core of neurodegeneration. Neural Regen. Res. 18, 1186–1190 (2023).

    Article  CAS  PubMed  Google Scholar 

  220. Yang, J., Zhao, Z., Gu, M., Feng, X. & Xu, H. Release and uptake mechanisms of vesicular Ca2+ stores. Protein Cell 10, 8–19 (2019).

    Article  CAS  PubMed  Google Scholar 

  221. Ogunbayo, O. A. et al. mTORC1 controls lysosomal Ca2+ release through the two-pore channel TPC2. Sci. Signal. 11, eaao5775 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  222. Thakore, P. et al. TRPML1 channels initiate Ca2+ sparks in vascular smooth muscle cells. Sci. Signal. https://doi.org/10.1126/scisignal.aba1015 (2020).

  223. Griffin, C. S. et al. The intracellular Ca2+ release channel TRPML1 regulates lower urinary tract smooth muscle contractility. Proc. Natl Acad. Sci. USA 117, 30775–30786 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  224. Li, G. & Li, P. L. Lysosomal TRPML1 channel: implications in cardiovascular and kidney diseases. Adv. Exp. Med. Biol. 1349, 275–301 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  225. Scotto Rosato, A. et al. TRPML1 links lysosomal calcium to autophagosome biogenesis through the activation of the CaMKKβ/VPS34 pathway. Nat. Commun. 10, 5630 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  226. Kilpatrick, B. S. Connecting Ca2+ and lysosomes to Parkinson disease. Messenger 5, 76–86 (2016).

    Article  PubMed  Google Scholar 

  227. Kilpatrick, B. S. et al. Endoplasmic reticulum and lysosomal Ca2+ stores are remodelled in GBA1-linked Parkinson disease patient fibroblasts. Cell Calcium 59, 12–20 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  228. Hui, L. et al. Acidifying endolysosomes prevented low-density lipoprotein-induced amyloidogenesis. J. Alzheimers Dis. 67, 393–410 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  229. Somogyi, A. et al. The synthetic TRPML1 agonist ML-SA1 rescues Alzheimer-related alterations of the endosomal–autophagic–lysosomal system. J. Cell Sci. 136, jcs259875 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  230. Drobny, A. et al. The role of lysosomal cathepsins in neurodegeneration: mechanistic insights, diagnostic potential and therapeutic approaches. Biochim. Biophys. Acta Mol. Cell Res. 1869, 119243 (2022).

    Article  CAS  PubMed  Google Scholar 

  231. Samie, M. A. & Xu, H. Lysosomal exocytosis and lipid storage disorders. J. Lipid Res. 55, 995–1009 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  232. Hoglinger, D. et al. NPC1 regulates ER contacts with endocytic organelles to mediate cholesterol egress. Nat. Commun. 10, 4276 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  233. Tancini, B. et al. Insight into the role of extracellular vesicles in lysosomal storage disorders. Genes 10, 510 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  234. Lloyd-Evans, E. & Platt, F. M. Lipids on trial: the search for the offending metabolite in Niemann–Pick type C disease. Traffic 11, 419–428 (2010).

    Article  CAS  PubMed  Google Scholar 

  235. Wheeler, S., Schmid, R. & Sillence, D. J. Lipid–protein interactions in Niemann–Pick type C disease: insights from molecular modeling. Int. J. Mol. Sci. 20, 717 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  236. Butterfield, D. A., Gu, L., Di Domenico, F. & Robinson, R. A. Mass spectrometry and redox proteomics: applications in disease. Mass. Spectrom. Rev. 33, 277–301 (2014).

    Article  CAS  PubMed  Google Scholar 

  237. Di Domenico, F. et al. Redox proteomics analyses of the influence of co-expression of wild-type or mutated LRRK2 and Tau on C. elegans protein expression and oxidative modification: relevance to Parkinson disease. Antioxid. Redox Signal. 17, 1490–1506 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  238. Yang, D. S. et al. Defective macroautophagic turnover of brain lipids in the TgCRND8 Alzheimer mouse model: prevention by correcting lysosomal proteolytic deficits. Brain 137, 3300–3318 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  239. Cox, T. M. Lysosomal diseases and neuropsychiatry: opportunities to rebalance the mind. Front. Mol. Biosci. 7, 177 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  240. Matutino Santos, P., Pereira Campos, G. & Nascimento, C. Endo-lysosomal and autophagy pathway and ubiquitin-proteasome system in mood disorders: a review article. Neuropsychiatr. Dis. Treat. 19, 133–151 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  241. Chu, C. T. Autophagic stress in neuronal injury and disease. J. Neuropathol. Exp. Neurol. 65, 423–432 (2006).

    Article  PubMed  Google Scholar 

  242. Kang, R., Zeh, H. J., Lotze, M. T. & Tang, D. The Beclin 1 network regulates autophagy and apoptosis. Cell Death Differ. 18, 571–580 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  243. Park, H., Kang, J. H. & Lee, S. Autophagy in neurodegenerative diseases: a hunter for aggregates. Int. J. Mol. Sci. 21, 3369 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  244. Dehay, B. et al. Pathogenic lysosomal depletion in Parkinson’s disease. J. Neurosci. 30, 12535–12544 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  245. Papadopoulos, C. & Meyer, H. Detection and clearance of damaged lysosomes by the endo-lysosomal damage response and lysophagy. Curr. Biol. 27, R1330–R1341 (2017).

    Article  CAS  PubMed  Google Scholar 

  246. Alu, A. et al. The role of lysosome in regulated necrosis. Acta Pharm. Sin. B. 10, 1880–1903 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  247. Ketterer, S. et al. Inherited diseases caused by mutations in cathepsin protease genes. FEBS J. 284, 1437–1454 (2017).

    Article  CAS  PubMed  Google Scholar 

  248. Perluigi, M., Di Domenico, F. & Butterfield, D. A. Oxidative damage in neurodegeneration: roles in the pathogenesis and progression of Alzheimer disease. Physiol. Rev. 104, 103–197 (2024).

    Article  CAS  PubMed  Google Scholar 

  249. Perry, G., Cash, A. D. & Smith, M. A. Alzheimer disease and oxidative stress. J. Biomed. Biotechnol. 2, 120–123 (2002).

    PubMed  PubMed Central  Google Scholar 

  250. J., S. Does high iron push a person with pathology into dementia? ALZFORUM https://www.alzforum.org/news/research-news/does-high-iron-push-person-pathology-dementia (2019).

  251. Zhang, G. et al. The potential role of ferroptosis in Alzheimer’s disease. J. Alzheimers Dis. 80, 907–925 (2021).

    Article  PubMed  Google Scholar 

  252. Sheftel, A. D., Zhang, A. S., Brown, C., Shirihai, O. S. & Ponka, P. Direct interorganellar transfer of iron from endosome to mitochondrion. Blood 110, 125–132 (2007).

    Article  CAS  PubMed  Google Scholar 

  253. Ashraf, A., Clark, M. & So, P. W. The aging of iron man. Front. Aging Neurosci. 10, 65 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  254. Schubert, D. & Chevion, M. The role of iron in β-amyloid toxicity. Biochem. Biophys. Res. Commun. 216, 702–707 (1995).

    Article  CAS  PubMed  Google Scholar 

  255. Smith, M. A. & Perry, G. Free radical damage, iron, and Alzheimer’s disease. J. Neurol. Sci. 134, 92–94 (1995).

    Article  PubMed  Google Scholar 

  256. Yambire, K. F. et al. Impaired lysosomal acidification triggers iron deficiency and inflammation in vivo. eLife 8, e51031 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  257. Ou, M. et al. Role and mechanism of ferroptosis in neurological diseases. Mol. Metab. 61, 101502 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  258. Pensalfini, A. et al. Intracellular amyloid and the neuronal origin of Alzheimer neuritic plaques. Neurobiol. Dis. 71, 53–61 (2014).

    Article  CAS  PubMed  Google Scholar 

  259. Eckman, E. A. et al. Nascent Aβ42 fibrillization in synaptic endosomes precedes plaque formation in a mouse model of Alzheimer’s-like β-amyloidosis. J. Neurosci. 43, 8812–8824 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  260. Decressac, M. et al. TFEB-mediated autophagy rescues midbrain dopamine neurons from α-synuclein toxicity. Proc. Natl Acad. Sci. USA 110, E1817–E1826 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  261. Siddiqi, F. H. et al. Felodipine induces autophagy in mouse brains with pharmacokinetics amenable to repurposing. Nat. Commun. 10, 1817 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  262. Young, M. M. et al. Autophagosomal membrane serves as platform for intracellular death-inducing signaling complex (iDISC)-mediated caspase-8 activation and apoptosis. J. Biol. Chem. 287, 12455–12468 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  263. Maetzel, D. et al. Genetic and chemical correction of cholesterol accumulation and impaired autophagy in hepatic and neural cells derived from Niemann–Pick type C patient-specific iPS cells. Stem Cell Rep. 2, 866–880 (2014).

    Article  CAS  Google Scholar 

  264. Elrick, M. J., Yu, T., Chung, C. & Lieberman, A. P. Impaired proteolysis underlies autophagic dysfunction in Niemann–Pick type C disease. Hum. Mol. Genet. 21, 4876–4887 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  265. Song, J. X. et al. HMGB1 is involved in autophagy inhibition caused by SNCA/α-synuclein overexpression: a process modulated by the natural autophagy inducer corynoxine B. Autophagy 10, 144–154 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  266. Fujii, T. et al. Parkinson’s disease-associated ATP13A2/PARK9 functions as a lysosomal H+,K+-ATPase. Nat. Commun. 14, 2174 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  267. Menzies, F. M. et al. Autophagy and neurodegeneration: pathogenic mechanisms and therapeutic opportunities. Neuron 93, 1015–1034 (2017).

    Article  CAS  PubMed  Google Scholar 

  268. Boland, B. et al. Promoting the clearance of neurotoxic proteins in neurodegenerative disorders of ageing. Nat. Rev. Drug Discov. 17, 660–688 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  269. Morawe, M. P. et al. Pharmacological mTOR-inhibition facilitates clearance of AD-related tau aggregates in the mouse brain. Eur. J. Pharmacol. 934, 175301 (2022).

    Article  CAS  PubMed  Google Scholar 

  270. Majumder, S., Richardson, A., Strong, R. & Oddo, S. Inducing autophagy by rapamycin before, but not after, the formation of plaques and tangles ameliorates cognitive deficits. PLoS ONE 6, e25416 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  271. Settembre, C. et al. TFEB links autophagy to lysosomal biogenesis. Science 332, 1429–1433 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  272. Wang, H., Zhu, Y., Liu, H., Liang, T. & Wei, Y. Advances in drug discovery targeting lysosomal membrane proteins. Pharmaceuticals 16, 601 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  273. Xue, W., Zhang, J. & Li, Y. Enhancement of lysosome biogenesis as a potential therapeutic approach for neurodegenerative diseases. Neural Regen. Res. 18, 2370–2376 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  274. Peng, W., Minakaki, G., Nguyen, M. & Krainc, D. Preserving lysosomal function in the aging brain: insights from neurodegeneration. Neurotherapeutics 16, 611–634 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  275. Bonam, S. R., Wang, F. & Muller, S. Lysosomes as a therapeutic target. Nat. Rev. Drug Discov. 18, 923–948 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  276. Lee, J. H. et al. β2-Adrenergic agonists rescue lysosome acidification and function in PSEN1 deficiency by reversing defective ER-to-lysosome delivery of ClC-7. J. Mol. Biol. 432, 2633–2650 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  277. Yang, D. S. et al. Reversal of autophagy dysfunction in the TgCRND8 mouse model of Alzheimer’s disease ameliorates amyloid pathologies and memory deficits. Brain 134, 258–277 (2011).

    Article  PubMed  Google Scholar 

  278. Cason, S. E. et al. Sequential dynein effectors regulate axonal autophagosome motility in a maturation-dependent pathway. J. Cell Biol. 220, e202010179 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  279. Forgac, M. Vacuolar ATPases: rotary proton pumps in physiology and pathophysiology. Nat. Rev. Mol. Cell Biol. 8, 917–929 (2007).

    Article  CAS  PubMed  Google Scholar 

  280. Checler, F., Afram, E., Pardossi-Piquard, R. & Lauritzen, I. Is γ-secretase a beneficial inactivating enzyme of the toxic APP C-terminal fragment C99? J. Biol. Chem. 296, 100489 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  281. Bourgeois, A. et al. Intraneuronal accumulation of C99 contributes to synaptic alterations, apathy-like behavior, and spatial learning deficits in 3xTgAD and 2xTgAD mice. Neurobiol. Aging 71, 21–31 (2018).

    Article  CAS  PubMed  Google Scholar 

  282. Jin, L. W., Shie, F. S., Maezawa, I., Vincent, I. & Bird, T. Intracellular accumulation of amyloidogenic fragments of amyloid-β precursor protein in neurons with Niemann–Pick type C defects is associated with endosomal abnormalities. Am. J. Pathol. 164, 975–985 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  283. Holsinger, R. M., McLean, C. A., Beyreuther, K., Masters, C. L. & Evin, G. Increased expression of the amyloid precursor β-secretase in Alzheimer’s disease. Ann. Neurol. 51, 783–786 (2002).

    Article  CAS  PubMed  Google Scholar 

  284. Tian, Y., Bustos, V., Flajolet, M. & Greengard, P. A small-molecule enhancer of autophagy decreases levels of Aβ and APP-CTF via Atg5-dependent autophagy pathway. FASEB J. 25, 1934–1942 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  285. Lauritzen, I., Pardossi-Piquard, R., Bourgeois, A., Bécot, A. & Checler, F. Does intraneuronal accumulation of carboxyl-terminal fragments of the amyloid precursor protein trigger early neurotoxicity in Alzheimer’s disease? Curr. Alzheimer Res. 16, 453–457 (2019).

    Article  CAS  PubMed  Google Scholar 

  286. Lardelli, M. An alternative view of familial Alzheimer’s disease genetics. J. Alzheimers Dis. 96, 13–39 (2023).

    Article  CAS  PubMed  Google Scholar 

  287. Vaillant-Beuchot, L. et al. Accumulation of amyloid precursor protein C-terminal fragments triggers mitochondrial structure, function, and mitophagy defects in Alzheimer’s disease models and human brains. Acta Neuropathol. 141, 39–65 (2021).

    Article  CAS  PubMed  Google Scholar 

  288. Fukumoto, H., Cheung, B. S., Hyman, B. T. & Irizarry, M. C. β-Secretase protein and activity are increased in the neocortex in Alzheimer disease. Arch. Neurol. 59, 1381–1389 (2002).

    Article  PubMed  Google Scholar 

  289. Ahmed, R. R. et al. BACE1 and BACE2 enzymatic activities in Alzheimer’s disease. J. Neurochem. 112, 1045–1053 (2010).

    Article  CAS  PubMed  Google Scholar 

  290. Kim, H. S. et al. Carboxyl-terminal fragment of Alzheimer’s APP destabilizes calcium homeostasis and renders neuronal cells vulnerable to excitotoxicity. FASEB J. 14, 1508–1517 (2000).

    CAS  PubMed  Google Scholar 

  291. Takasugi, N. et al. The pursuit of the “inside” of the amyloid hypothesis — is C99 a promising therapeutic target for Alzheimer’s disease? Cells 12, 454 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  292. Pera, M. et al. MAM and C99, key players in the pathogenesis of Alzheimer’s disease. Int. Rev. Neurobiol. 154, 235–278 (2020).

    Article  CAS  PubMed  Google Scholar 

  293. Patel, S., Yuan, Y., Gunaratne, G. S., Rahman, T. & Marchant, J. S. Activation of endo-lysosomal two-pore channels by NAADP and PI(3,5)P2. Five things to know. Cell Calcium 103, 102543 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  294. Lu, Y., Hao, B., Graeff, R. & Yue, J. NAADP/TPC2/Ca2+ signaling inhibits autophagy. Commun. Integr. Biol. 6, e27595 (2013).

    Article  PubMed  Google Scholar 

  295. Moriyama, Y., Maeda, M. & Futai, M. Involvement of a non-proton pump factor (possibly Donnan-type equilibrium) in maintenance of an acidic pH in lysosomes. FEBS Lett. 302, 18–20 (1992).

    Article  CAS  PubMed  Google Scholar 

  296. Grabe, M. & Oster, G. Regulation of organelle acidity. J. Gen. Physiol. 117, 329–344 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  297. Guerrero-Navarro, L., Jansen-Dürr, P. & Cavinato, M. Age-related lysosomal dysfunctions. Cells 11, 1977 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  298. Fischer, P.-D. D. Oskar Miliare Nekrosen mit drusigen Wucherungen der Neurofibrillen, eine regelmässige Veränderung der Hirnrinde bei seniler Demenz [German]. Monatsschrift f.ür. Psychiatr. und Neurologie. 22, 361–372 (1907).

    Article  Google Scholar 

  299. Puri, C. et al. The RAB11A-positive compartment is a primary platform for autophagosome assembly mediated by WIPI2 recognition of PI3P-RAB11A. Dev. Cell. 45, 114–131.e8 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  300. Gomez-Sanchez, R., Tooze, S. A. & Reggiori, F. Membrane supply and remodeling during autophagosome biogenesis. Curr. Opin. Cell Biol. 71, 112–119 (2021).

    Article  CAS  PubMed  Google Scholar 

  301. Zheng, Q. et al. Calcium transients on the ER surface trigger liquid–liquid phase separation of FIP200 to specify autophagosome initiation sites. Cell 185, 4082–4098.e22 (2022).

    Article  CAS  PubMed  Google Scholar 

  302. Osawa, T., Matoba, K. & Noda, N. N. Lipid transport from endoplasmic reticulum to autophagic membranes. Cold Spring Harb. Perspect. Biol. 14, a041254 (2022).

    Article  CAS  PubMed  Google Scholar 

  303. Li, S. et al. A new type of ERGIC–ERES membrane contact mediated by TMED9 and SEC12 is required for autophagosome biogenesis. Cell Res. 32, 119–138 (2022).

    Article  PubMed  Google Scholar 

  304. Kumar, S. et al. Mammalian hybrid pre-autophagosomal structure HyPAS generates autophagosomes. Cell 184, 5950–5969.e22 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  305. Jahreiss, L., Menzies, F. M. & Rubinsztein, D. C. The itinerary of autophagosomes: from peripheral formation to kiss-and-run fusion with lysosomes. Traffic 9, 574–587 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  306. Zhao, Y. G., Codogno, P. & Zhang, H. Machinery, regulation and pathophysiological implications of autophagosome maturation. Nat. Rev. Mol. Cell Biol. 22, 733–750 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  307. Liang, W. et al. Mitochondria are secreted in extracellular vesicles when lysosomal function is impaired. Nat. Commun. 14, 5031 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  308. Heckmann, B. L. et al. LC3-associated endocytosis facilitates β-amyloid clearance and mitigates neurodegeneration in murine Alzheimer’s disease. Cell 183, 1733–1734 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  309. Deretic, V. et al. Membrane atg8ylation in canonical and noncanonical autophagy. J. Mol. Biol. https://doi.org/10.1016/j.jmb.2024.168532 (2024).

  310. Almeida, M. F., Bahr, B. A. & Kinsey, S. T. Endosomal–lysosomal dysfunction in metabolic diseases and Alzheimer’s disease. Int. Rev. Neurobiol. 154, 303–324 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  311. Qureshi, Y. H., Baez, P. & Reitz, C. Endosomal trafficking in Alzheimer’s disease, Parkinson’s disease, and neuronal ceroid lipofuscinosis. Mol. Cell Biol. 40 e00262–20 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  312. Winckler, B. et al. The endolysosomal system and proteostasis: from development to degeneration. J. Neurosci. 38, 9364–9374 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  313. Small, S. A. & Petsko, G. A. Retromer in Alzheimer disease, Parkinson disease and other neurological disorders. Nat. Rev. Neurosci. 16, 126–132 (2015).

    Article  CAS  PubMed  Google Scholar 

  314. Mathews, P. M. & Levy, E. Exosome production is key to neuronal endosomal pathway integrity in neurodegenerative diseases. Front. Neurosci. 13, 1347 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  315. Izco, M., Carlos, E. & Alvarez-Erviti, L. Impact of endolysosomal dysfunction upon exosomes in neurodegenerative diseases. Neurobiol. Dis. 166, 105651 (2022).

    Article  CAS  PubMed  Google Scholar 

  316. Annunziata, I. et al. Lysosomal NEU1 deficiency affects amyloid precursor protein levels and amyloid-β secretion via deregulated lysosomal exocytosis. Nat. Commun. 4, 2734 (2013).

    Article  PubMed  Google Scholar 

  317. Bodzeta, A., Kahms, M. & Klingauf, J. The presynaptic v-ATPase reversibly disassembles and thereby modulates exocytosis but is not part of the fusion machinery. Cell Rep. 20, 1348–1359 (2017).

    Article  CAS  PubMed  Google Scholar 

  318. Schiapparelli, L. M. et al. Proteomic screen reveals diverse protein transport between connected neurons in the visual system. Cell Rep. 38, 110287 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  319. Bae, E. J. et al. Haploinsufficiency of cathepsin D leads to lysosomal dysfunction and promotes cell-to-cell transmission of α-synuclein aggregates. Cell Death Dis. 6, e1901 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

Research in the Nixon laboratory has been supported by grants (P01 AG017617; R01 AG062376) from the National Institute on Aging, New Vision Research Foundation (Leonard Litwin Scholar award), Cure Huntington’s Disease Initiative (CHDI) Foundation, Takeda Corp. and Johnson & Johnson. D.C.R. received funding from the UK Dementia Research Institute (funded by the MRC, Alzheimer’s Research UK and the Alzheimer’s Society), Parkinson’s UK, the National Institute for Health and Care Research (NIHR) Cambridge Biomedical Research Centre (NIHR203312), Rosetrees Trust and the Tau Consortium/Rainwater Charitable Foundation. The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. The authors acknowledge the expert assistance of S. Jain in preparing this manuscript for publication. They thank G. Di Paolo and A. Henry for critical reading of the manuscript and suggestions. The authors appreciate additional contributions made to the subjects reviewed that regretfully could not be cited due to space and reference limitations.

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Authors and Affiliations

  1. Center for Dementia Research, Nathan Kline Institute, Orangeburg, New York, NY, USA

    Ralph A. Nixon

  2. Department of Psychiatry, New York University Grossman School of Medicine, New York, NY, USA

    Ralph A. Nixon

  3. Department of Cell Biology, New York University Grossman School of Medicine, New York, NY, USA

    Ralph A. Nixon

  4. Neuroscience Institute, New York University Grossman School of Medicine, New York, NY, USA

    Ralph A. Nixon

  5. Department of Medical Genetics, Cambridge Institute for Medical Research, Cambridge, UK

    David C. Rubinsztein

  6. UK Dementia Research Institute, University of Cambridge, Cambridge Institute for Medical Research, Cambridge, UK

    David C. Rubinsztein

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Correspondence to Ralph A. Nixon.

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D.C.R. is a consultant for Aladdin Healthcare Technologies Ltd, Mindrank AI, Nido Biosciences, Drishti Discoveries, Retro Biosciences, PAQ Therapeutics and Alexion Pharma Intl Ops Ltd. R.A.N. declares no competing interests.

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Glossary

α-Synuclein

A highly soluble neuronal protein that regulates synaptic vesicle trafficking and subsequent neurotransmitter release, and accumulates in Lewy bodies and Lewy neurites in Parkinson disease (PD) and other synucleinopathies. Mutations of α-synuclein are linked to familial PD.

β-Amyloid precursor protein

(APP). A single-pass transmembrane protein highly expressed in the brain but of mainly unknown function. APP undergoes rapid cleavage into multiple bioactive products by sequential proteases, including the intramembranous γ-secretase complex that generates β-carboxy-terminal fragment (βCTF) and amyloid-β, two polypeptides implicated in Alzheimer disease (AD) pathogenesis and overproduced by APP mutations that cause autosomal dominant AD.

Alzheimer disease

(AD). The most common form of dementia involving neurodegeneration of brain regions controlling thought, memory and language. AD progresses from memory loss to impaired language expression, comprehension and inability to perform activities of daily living. Autosomal dominant gene mutations (β-amyloid precursor protein (APP), presenilin 1 (PSEN1), PSEN2) induce adult early-onset (age <65 years) AD, whereas most cases are late-onset (age >65 years) AD involving influences of varied genetic and environmental risk factors.

Conjugation of ATG8 (LC3) family membranes to single membranes

(CASM). A non-canonical autophagy pathway that shares some of the common ATG machinery but bears key mechanistic and functional distinctions, and is characterized by conjugation of ATG8 (LC3) to single membranes such as lysosomes and phagosomes.

Endolysosomal escape

Escape of substrates from vesicles in the endocytic and lysosomal systems.

Endoplasmic reticulum-associated degradation

(ERAD). The recognition of substrates in the lumen and membrane of the endoplasmic reticulum (ER), and their translocation into the cytosol, ubiquitination and delivery to the proteasome for degradation.

Exosomes

Membrane-bound extracellular vesicles that are produced in the endosomal compartment of eukaryotic cells.

Frontotemporal lobar degeneration

(FTLD). Also known as Pick disease. A group of brain disorders caused by degeneration of the frontal and anterior temporal lobes of the brain and characterized by progressive decline in behaviour (for example, personality changes, apathy) or movement, speaking or language comprehension.

Huntingtin

A ubiquitously expressed protein with varied roles in synaptic transmission, transport and cell survival. Abnormal expansion of a glutamine stretch (polyQ) in mutant huntingtin causes Huntington disease (HD).

Huntington disease

(HD). A monogenic neurodegenerative disorder caused by the huntingtin gene, HTT, characterized by loss of striatal neurons, and resulting in motor, psychiatric and cognitive symptoms.

Induced pluripotent stem cells

A type of stem cells derived from adult somatic cells which have been reprogrammed through inducing genes and factors to be pluripotent.

LC3 family members

Members of the ATG8 gene family that are classical markers for autophagosomes

Lewy body dementia

(LBD). A progressive dementia involving a decline in thinking, movement, behaviour and mood and associated with abnormal deposits of α-synuclein in the brain, called Lewy bodies.

Lysosomal storage disorder

(LSD). A group of more than 50 mainly childhood disorders that are inborn errors of metabolism characterized by abnormal accumulation of substrates due to defective lysosomes and usually involving deficiency of a single lipid metabolizing enzyme.

Micropinocytosis

A process in which macromolecules are engulfed by small vesicles from the plasma membrane.

Microvesicles

Diverse membrane‐enclosed vesicles that are released from cells into the extracellular space.

Neuronal ceroid lipofuscinosis

(NCL). Also called Batten disease. A group of 14 inherited lysosomal storage disorders (LSDs) characterized by intracellular accumulation of autofluorescent lipopigment (ceroid and lipofuscin) and progressive neurodegeneration.

Nucleoid

A structure comprising mitochondrial DNA (mtDNA) and numerous nucleoid-associated proteins that enables submitochondrial organization of mtDNA.

Parkinson disease

(PD). A chronic degenerative disorder targeting dopaminergic neural circuits and initially causing tremors, rigidity and slowed movement, and later additional intellectual functions, including dementia in a minor population of affected individuals.

Presenilin 1

(PSEN1). A multifunctional transmembrane protein that, in loss-of-function mutant form, is one of three autosomal dominant causes of Alzheimer disease (AD). PSEN1 is one of four core proteins in the γ-secretase endoprotease complex that performs intramembrane cleavage of dozens of integral membrane proteins, including β-amyloid precursor protein (APP) that sequentially generates the β-carboxy-terminal fragment (βCTF) and amyloid-β, two polypeptides implicated in AD pathogenesis.

Ryanodine receptors

(RyRs). Ion channels residing in the sarcoplasmic/endoplasmic reticulum membrane and responsible for Ca2+ release from intracellular stores in excitable tissues, such as muscles and neurons.

Tau

(MAPT). A group of six highly soluble protein isoforms produced by alternative splicing from MAPT that help stabilize the microtubule cytoskeleton of neurons and compose neurofibrillary tangles, a hallmark of Alzheimer disease (AD).

TFEB, TFE3

Members of the MiT-TFE family of helix–loop–helix leucine zipper transcription factors that regulate expression of genes involved in the biogenesis and function of lysosomes and autophagosomes.

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Nixon, R.A., Rubinsztein, D.C. Mechanisms of autophagy–lysosome dysfunction in neurodegenerative diseases. Nat Rev Mol Cell Biol (2024). https://doi.org/10.1038/s41580-024-00757-5

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