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Endosomal sorting and trafficking, the retromer complex and neurodegeneration

Molecular Psychiatry volume 24, pages 857–868 (2019)Cite this article

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Abstract

The retromer is a highly conserved multimeric protein complex present in all eukaryotic cells whose activity is essential for regulating the recycling and retrieval of numerous protein cargos from the endosome to trans-Golgi network or the cell surface. In recent years, molecular and genomic studies have provided evidence that aberrant regulation of endosomal protein sorting and trafficking secondary to a dysfunction of the retromer complex could be implicated in the pathogenesis of several neurodegenerative diseases. Thus, deficiency or mutations in one or more protein components of the retromer leads to increased accumulation of protein aggregates, as well as enhanced cellular neurotoxicity. In this review, we will discuss the structure and function of the retromer complex and its neurobiology, its relevance to key molecules involved in neurodegeneration and the potential role that it plays in the development of two major neurodegenerative disorders, Parkinson’s disease and Alzheimer’s disease. Finally, we will discuss the viability of targeting the retromer via pharmacological chaperones or genetic approaches to enhance or restore its function as a novel and unifying disease-modifying strategy against these diseases.

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References

  1. Miaczynska M, Pelkmans L, Zerial M. Not just a sink: endosomes in control of signal transduction. Curr Opin Cell Biol. 2004;16:400–6.

    CAS  PubMed  Google Scholar 

  2. Neefjes J, van der Kant R. Stuck in traffic: an emerging theme in diseases of the nervous system. Trends Neurosci. 2014;37:66–76.

    CAS  PubMed  Google Scholar 

  3. Small SA, Simoes-Spassov S, Mayeux R, Petsko GA. Endosomal traffic jams represent a pathogenic hub and therapeutic target in Alzheimer’s disease. Trends Neurosci. 2017;40:592–602.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Lamb CA, Dooley HC, Tooze SA. Endocytosis and autophagy: shared machinery for degradation. Bioessays. 2013;35:34–45.

    CAS  PubMed  Google Scholar 

  5. Scott CC, Vacca F, Gruenberg J. Endosome maturation, transport and functions. Semin Cell Dev Biol. 2014;31:2–10.

    CAS  PubMed  Google Scholar 

  6. Hurley JH, Emr SD. The ESCRT complexes: structure and mechanism of a membrane-trafficking network. Annu Rev Biophys Biomol Struct. 2006;35:277–98.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Kimura N, Yanagisawa K. Traffic jam hypothesis: relationship between endocytic dysfunction and Alzheimer’s disease. Neurochem Int. 2017;17:30249–508.

    Google Scholar 

  8. Huotari J, Helenius A. Endosome maturation. EMBO J. 2011;30:3481–500.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Chi RJ, Harrison MS, Burd CG. Biogenesis of endosome-derived transport carriers. Cell Mol Life Sci. 2015;72:3441–55.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Bonifacino JS, Hurley JH. Retromer. Curr Opin Cell Biol. 2008;20:427–36.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. McGough IJ, Cullen PJ. Recent advances in retromer biology. Traffic. 2011;12:963–71.

    CAS  PubMed  Google Scholar 

  12. Seaman MN. The retromer complex - endosomal protein recycling and beyond. J Cell Sci. 2012;125:4693–702.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Lucas M, Hierro A. Retromer. Curr Biol. 2017;27:R687–9.

    CAS  PubMed  Google Scholar 

  14. Seaman MN, McCaffery JM, Emr SD. A membrane coat complex essential for endosome-to-Golgi retrograde transport in yeast. J Cell Biol. 1998;142:665–81.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Haft CR, de la Luz Sierra M, Bafford R, Lesniak MA, Barr VA, Taylor SI. Human orthologs of yeast vacuolar protein sorting proteins Vps26, 29, and 35: assembly into multimeric complexes. Mol Biol Cell. 2000;11:4105–16.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Seaman MN. Cargo-selective endosomal sorting for retrieval to the Golgi requires retromer. J Cell Biol. 2004;165:111–22.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Burd C, Cullen PJ. Retromer: a master conductor of endosome sorting. Cold Spring Harb Perspect Biol. 2014;6:a016774.

    PubMed  PubMed Central  Google Scholar 

  18. Wassmer T, Attar N, Harterink M, van Weering JR, Traer CJ, Oakley J, Goud B, et al. The retromer coat complex coordinates endosomal sorting and dynein-mediated transport, with carrier recognition by the trans-Golgi network. Dev Cell. 2009;17:110–22.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Harbour ME, Breusegem SY, Antrobus R, Freeman C, Reid E, Seaman MN. The cargo-selective retromer complex is a recruiting hub for protein complexes that regulate endosomal tubule dynamics. J Cell Sci. 2010;123:3703–17.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Wang S, Bellen HJ. The retromer complex in development and disease. Dev Camb Engl. 2015;142:2392–6.

    CAS  Google Scholar 

  21. Sadigh-Eteghad S, Askari-Nejad MS, Mahmoudi J, Majdi A. Cargo trafficking in Alzheimer’s disease: the possible role of retromer. Neurol Sci. 2016;37:17–22.

    PubMed  Google Scholar 

  22. Harterink M, Port F, Lorenowicz MJ, McGough IJ, Silhankova M, Betist MC, et al. A SNX3-dependent retromer pathway mediates retrograde transport of the Wnt sorting receptor Wntless and is required for Wnt secretion. Nat Cell Biol. 2011;13:914–23.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Hierro A, Rojas AL, Rojas R, Murthy N, Effantin G, Kajava AV, et al. Functional architecture of the retromer cargo-recognition complex. Nature. 2007;449:1063–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Klinger SC, Siupka P, Nielsen MS. Retromer-mediated trafficking of transmembrane receptors and transporters. Membranes. 2015;5:288–306.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Temkin P, Lauffer B, Jäger S, Cimermancic P, Krogan NJ, von Zastrow M. SNX27 mediates retromer tubule entry and endosome-to-plasma membrane trafficking of signalling receptors. Nat Cell Biol. 2011;13:715–21.

    PubMed  PubMed Central  Google Scholar 

  26. McGough IJ, Steinberg F, Gallon M, Yatsu A, Ohbayashi N, Heesom KJ, et al. Identification of molecular heterogeneity in SNX27-retromer-mediated endosome-to-plasma membrane recycling. J Cell Sci. 2014;127:4940–53.

    PubMed  PubMed Central  Google Scholar 

  27. Li C, Shah SZ, Zhao D, Yang L. Role of the retromer complex in neurodegenerative diseases. Front Aging Neurosci. 2016;8:42.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Harbour ME, Breusegem SY, Seaman MN. Recruitment of the endosomal WASH complex is mediated by the extended “tail” of Fam21 binding to the retromer protein Vps35. Biochem J. 2012;442:209–20.

    CAS  PubMed  Google Scholar 

  29. Arighi CN, Hartnell LM, Aguilar RC, Haft CR, Bonifacino JS. Role of the mammalian retromer in sorting of the cation-independent mannose 6-phosphate receptor. J Cell Biol. 2004;165:123–33.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Kim E, Lee Y, Lee HJ, Kim JS, Song BS, Huh JW, et al. Implication of mouse Vps26b-Vps29-Vps35 retromer complex in sortilin trafficking. Biochem Biophys Res Commun. 2010;403:167–71.

    CAS  PubMed  Google Scholar 

  31. Lucin KM, O’Brien CE, Bieri G, Czirr E, Mosher KI, Abbey RJ, et al. Microglial beclin 1 regulates retromer trafficking and phagocytosis and is impaired in Alzheimer’s disease. Neuron. 2013;79:873–86.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Small SA, Petsko GA. Retromer in Alzheimer disease, Parkinson disease and other neurological disorders. Nat Rev Neurosci. 2015;16:126–32.

    CAS  PubMed  Google Scholar 

  33. Abubakar YS, Zheng W, Olsson S, Zhou J. Updated insight into the physiological and pathological roles of the retromer complex. Int J Mol Sci. 2017;18:1601.

    PubMed Central  Google Scholar 

  34. Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, Dutra A, et al. Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science. 1997;276:2045–7.

    CAS  Google Scholar 

  35. Williams ET, Chen X, Moore DJ. VPS35, the retromer complex and Parkinson’s disease. J Parkinson’s Dis. 2017;7:219–33.

    CAS  Google Scholar 

  36. Vilarino-Guell C, Wider C, Ross O, Dachsel J, Kachergus J, Lincoln S, et al. VPS35 mutations in Parkinson disease. Am J Hum Genet. 2011;89:162–7.

    PubMed  PubMed Central  Google Scholar 

  37. MacLeod DA, Rhinn H, Kuwahara T, Zolin A, Di Paolo G, McCabe BD, et al. RAB7L1 interacts with LRRK2 to modify intraneuronal protein sorting and Parkinson’s disease risk. Neuron. 2013;77:425–39.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Zhao Y, Perera G, Takahashi-Fujigasaki J, Mash DC, Vonsattel J-P G, Uchino A,  et al. Reduced LRRK2 in association with retromer dysfunction in post-mortem brain tissue from LRRK2 mutation carriers. Brain. 2018; 141:486-495

    PubMed Central  Google Scholar 

  39. Wen L, Tang FL, Hong Y, Luo SW, Wang CL, He W, et al. VPS35 haploinsufficiency increases Alzheimer’s disease neuropathology. J Cell Biol. 2011;195:765–79.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Miura E, Hasegawa T, Konno M, Suzuki M, Sugeno N, Fujikake N, et al. VPS35 dysfunction impairs lysosomal degradation of alpha-synuclein and exacerbates neurotoxicity in a Drosophila model of Parkinson’s disease. Neurobiol Dis. 2014;71:1–13.

    CAS  PubMed  Google Scholar 

  41. Munsie LN, Milnerwood AJ, Seibler P, Beccano-Kelly DA, Tatarnikov I, Khinda J, et al. Retromer-dependent neurotransmitter receptor trafficking to synapses is altered by the Parkinson’s Disease VPS35 mutation p. D620N. Hum Mol Genet. 2015;24:1691–703.

    CAS  PubMed  Google Scholar 

  42. Follett J, Norwood SJ, Hamilton NA, Mohan M, Kovtun O, Tay S, et al. The Vps35 D620N mutation linked to Parkinson’s disease disrupts the cargo sorting function of retromer. Traffic. 2014;15:230–44.

    CAS  PubMed  Google Scholar 

  43. Linhart R, Wong SA, Cao J, Tran M, Huynh A, Ardrey C, et al. Vacuolar protein sorting 35 (Vps35) rescues locomotor deficits and shortened lifespan in Drosophila expressing a Parkinson’s disease mutant of leucine-rich repeat kinase 2 (LRRK2). Mol Neurodegener. 2014;9:23.

    PubMed  PubMed Central  Google Scholar 

  44. Tang FL, Erion JR, Tian Y, Liu W, Yin DM, Ye J, et al. VPS35 in dopamine neurons is required for endosome-to-Golgi retrieval of Lamp2a, a receptor of chaperone-mediated autophagy that is critical for alpha-synuclein degradation and prevention of pathogenesis of Parkinson’s disease. J Neurosci. 2015;35:10613–28.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Tang FL, Liu W, Hu JX, Erion JR, Ye J, Mei L, Xiong WC. VPS35 deficiency or mutation causes dopaminergic neuronal loss by impairing mitochondrial fusion and function. Cell Rep. 2015;12:1631–43.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Ishizu N, Yui D, Hebisawa A, Aizawa H, Cui W, Fujita Y, et al. Impaired striatal dopamine release in homozygous Vps35 D620N knock-in mice. Hum Mol Genet. 2016;25:4507–17.

    CAS  PubMed  Google Scholar 

  47. Tsika E, Glauser L, Moser R, Fiser A, Daniel G, Sheerin UM, et al. Parkinson’s disease-linked mutations in VPS35 induce dopaminergic neurodegeneration. Hum Mol Genet. 2014;23:4621–38.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Klaips CL, Jayaraj GG, Hartl FU. Pathways of cellular proteostasis in aging and disease. J Cell Biol. 2018;217:51–63.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Zimprich A, Benet-Pagès A, Struhal W, Graf E, Eck SH, Offman MN, et al. A Mutation in VPS35, Encoding a Subunit of the Retromer Complex, Causes Late-Onset Parkinson Disease. The American Journal of Human Genetics. 2011; 89:168-175

    CAS  PubMed  Google Scholar 

  50. Gustavsson EK, Guella I, Trinh J, Szu-Tu C, Rajput A, Rajput AH, et al. Genetic variability of the retromer cargo recognition complex in parkinsonism. Movement Disorders. 2011; 30:580-584

    PubMed  Google Scholar 

  51. Shannon B, Soto-Ortolaza A, Rayaprolu S, Cannon HD, Labbé C, Benitez BA, et al. Genetic variation of the retromer subunits VPS26A/B-VPS29 in Parkinson's disease. Neurobiology of Aging. 2014; 35:1958.e1-1958.e2

  52. Gambardella S, Biagioni F, Ferese R, Busceti CL, Frati A, Novelli G, et al. Vacuolar Protein Sorting Genes in Parkinson's Disease: A Re-appraisal of Mutations Detection Rate and Neurobiology of Disease. Frontiers in Neuroscience. 2016; 10

  53. Follett J, Bugarcic A, Yang Z, Ariotti N,  Norwood SJ,  Collins BM, et al. Parkinson Disease-linked Vps35 R524W Mutation Impairs the Endosomal Association of Retromer and Induces α-Synuclein Aggregation. Journal of Biological Chemistry. 2016; 291:18283-18298

    CAS  PubMed  Google Scholar 

  54. Inoshita T, Arano T, Hosaka Y, Meng H, Umezaki Y, Kosugi S, et al. Vps35 in cooperation with LRRK2 regulates synaptic vesicle endocytosis through the endosomal pathway in Drosophila. Human Molecular Genetics. 2017; 26: 2933-2948

    CAS  PubMed  Google Scholar 

  55. Chung CY, Khurana V, Yi S, Sahni N, Loh KH, Auluck PK, et al. In Situ Peroxidase Labeling and Mass-Spectrometry Connects Alpha-Synuclein Directly to Endocytic Trafficking and mRNA Metabolism in Neurons. Cell Systems. 2017;4: 242–250.e4

    PubMed  PubMed Central  Google Scholar 

  56. Sowade RF, Jahn TR. Seed-induced acceleration of amyloid-β mediated neurotoxicity in vivo. Nat Commun. 2017;8:512.

    PubMed  PubMed Central  Google Scholar 

  57. Cataldo AM, Peterhoff CM, Troncoso JC, Gomez-Isla T, Hyman BT, Nixon RA. Endocytic pathway abnormalities precede amyloid beta deposition in sporadic Alzheimer’s disease and Down syndrome: differential effects of APOE genotype and presenilin mutations. Am J Pathol. 2000;157:277–86.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Small SA, Kent K, Pierce A, Leung C, Kang MS, Okada H, et al. Model-guided microarray implicates the retromer complex in Alzheimer’s disease. Ann Neurol. 2005;58:909–19.

    CAS  PubMed  Google Scholar 

  59. Vardarajan BN, Bruesegem SY, Harbour ME, Inzelberg R, Friedland R, St George-Hyslop P, et al. Identification of Alzheimer disease-associated variants in genes that regulate retromer function. Neurobiol Aging. 2012;33:2231.

    PubMed  PubMed Central  Google Scholar 

  60. Andersen OM, Reiche J, Schmidt V, Gotthardt M, Spoelgen R, Behlke J, et al. Neuronal sorting protein-related receptor sorLA/LR11 regulates processing of the amyloid precursor protein. Proc Natl Acad Sci USA. 2005;102:13461–6.

    CAS  PubMed  Google Scholar 

  61. Schmidt V, Sporbert A, Rohe M, Reimer T, Rehm A, Andersen OM, Willnow TE. SorLA/LR11 regulates processing of amyloid precursor protein via interaction with adaptors GGA and PACS-1. J Biol Chem. 2007;282:32956–64.

    CAS  PubMed  Google Scholar 

  62. Mehmedbasic A, Christensen SK, Nilsson J, Rüetschi U, Gustafsen C, Poulsen AS, et al. SorLA complement-type repeat domains protect the amyloid precursor protein against processing. J Biol Chem. 2015;290:3359–76.

    CAS  PubMed  Google Scholar 

  63. Lao A, Schmidt V, Schmitz Y, Willnow TE, Wolkenhauer O. Multi-compartmental modeling of SORLA’s influence on amyloidogenic processing in Alzheimer’s disease. BMC Syst Biol. 2012;6:74.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Caglayan S, Takagi-Niidome S, Liao F, Carlo AS, Schmidt V, Burgert T, et al. Lysosomal sorting of amyloid-β by the SORLA receptor is impaired by a familial Alzheimer’s disease mutation. Sci Transl Med. 2014;6:223ra20.

    PubMed  Google Scholar 

  65. Sager KL, Wuu J, Herskowitz JH, Mufson EJ, Levey AI, Lah JJ. Neuronal LR11 expression does not differentiate between clinically-defined Alzheimer’s disease and control brains. PLoS ONE. 2012;7:e40527.

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Liang X, Slifer M, Martin ER, Schnetz-Boutaud N, Barlett J, Anderson B, et al. Genomic convergence to identify candidate genes for Alzheimer’s disease on chromosome 10. Hum Mutat. 2009;30:463–71.

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Goodarzi MO, Lehaman DM, Taylor KD, Guo X, Cui J, Quinones MJ, et al. SORCS1: a novel human type 2-diabetes susceptibility gene suggested by the mouse. Diabetes. 2007;56:1922–9.

    CAS  PubMed  Google Scholar 

  68. Lane RF, Raines SM, Steele JW, Ehrlich ME, Lah JA, Small SA, et al. Diabetes-associated SorCS1 regulates Alzheimer’s amyloid-beta metabolism: evidence for involvement of SorL1 and the retromer complex. J Neurosci. 2010;30:13110–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Knight EM, Ruiz HH, Kim SH, Harte JC, Hsieh W, Glabe C, Klein WL, Attie AD, Buettner C, Ehrlich ME, Gandy S. Unexpected partial correction of metabolic and behavioral phenotypes of Alzheimer’s APP/PSEN1 mice by gene targeting of diabetes-Alzheimer’s-related Sorcs1. Acta Neuropath Commun. 2016;4:16.

    Google Scholar 

  70. Chu J, Praticò D. The retromer complex system in a transgenic mouse model of AD: influence of age. Neurobiol Aging. 2017;52:32–8.

    CAS  PubMed  Google Scholar 

  71. Wang Y, Mandelkow E. Tau in physiology and pathology. Nat Rev Neurosci. 2016;17:5–21.

    PubMed  Google Scholar 

  72. Wu JW, Herman M, Liu L, Simoes S, Acker CM, Figueroa H, et al. Small misfolded Tau species are internalized via bulk endocytosis and anterogradely and retrogradely transported in neurons. J Biol Chem. 2013;288:1856–70.

    CAS  PubMed  Google Scholar 

  73. Michel CH, Kumar S, Pinotsi D, Tunnacliffe A, St George-Hyslop P, Mandelkow E, et al. Extracellular monomeric tau protein is sufficient to initiate the spread of tau protein pathology. J Biol Chem. 2014;289:956–67.

    CAS  PubMed  Google Scholar 

  74. Siintola E, Partanen S, Strömme P, Haapanen A, Haltia M, Maehlen J, et al. Cathepsin D deficiency underlies congenital human neuronal ceroid-lipofuscinosis. Brain. 2006;129:1438–45.

    PubMed  Google Scholar 

  75. Steinfeld R, Reinhardt K, Schreiber K, Hillebrand M, Kraetzner R, Bruck W, et al. Cathepsin D deficiency is associated with a human neurodegenerative disorder. Am J Hum Genet. 2006;78:988–98.

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Khurana V, Elson-Schwab I, Fulga TA, Sharp KA, Loewen CA, Mulkearns E, et al. Lysosomal dysfunction promotes cleavage and neurotoxicity of tau in vivo. PLoS Genet. 2010;6:e1001026.

    PubMed  PubMed Central  Google Scholar 

  77. Rodriguez L, Mohamed NV, Desjardins A, Lippé R, Fon EA, Leclerc N. Rab7A regulates tau secretion. J Neurochem. 2017;141:592–605.

    CAS  PubMed  Google Scholar 

  78. Bucci C, Thomsen P, Nicoziani P, McCarthy J, van Deurs B. Rab7: a key to lysosome biogenesis. Mol Biol Cell. 2000;11:467–80.

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Rojas R, van Vlijmen T, Mardones GA, Prabhu Y, Rojas AL, Mohammed S, et al. Regulation of retromer recruitment to endosomes by sequential action of Rab5 and Rab7. J Cell Biol. 2008;183:513–26.

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Choy RW-Y, Park M, Temkin P, Herring BE, Marley A, Nicoll RA, von Zastrow M. Retromer mediates a discrete route of local membrane delivery to dendrites. Neuron. 2014;82:55–62.

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Temkin P, Morishita W, Goswami D, Arendt K, Chen L, Malenka R. The retromer supports AMPA receptor trafficking during LTP. Neuron. 2017;94:74–82.

    CAS  PubMed  Google Scholar 

  82. Sofroniew MV, Vinters HV. Astrocytes: biology and pathology. Acta Neuropathol. 2010;119:7–35.

    PubMed  Google Scholar 

  83. Eroglu C, Barres BA. Regulation of synaptic connectivity by glia. Nature. 2010;468:223–31.

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Pekny M, Wilhelmsson U, Pekna M. The dual role of astrocyte activation and reactive gliosis. Neurosci Lett. 2014;565:30–8.

    CAS  PubMed  Google Scholar 

  85. Söllvander S, Nikitidou E, Brolin R, Söderberg L, Sehlin D, Lannfelt L, Erlandsson A. Accumulation of amyloid-β by astrocytes result in enlarged endosomes and microvesicle-induced apoptosis of neurons. Mol Neurodegener. 2016;11:38.

    PubMed  PubMed Central  Google Scholar 

  86. Jay TR, von Saucken VE, Landreth GE. TREM2 in neurodegenerative diseases. Mol Neurodegener. 2017;12:56.

    PubMed  PubMed Central  Google Scholar 

  87. Kleinberger G, Yamanishi Y, Suárez-Calvet M, Czirr E, Lohmann E, Cuyvers E, et al. TREM2 mutations implicated in neurodegeneration impair cell surface transport and phagocytosis. Sci Transl Med. 2014;6:243ra86.

    PubMed  Google Scholar 

  88. Yin J, Liu X, He Q, Zhou L, Yuan Z, Zhao S. Vps35-dependent recycling of Trem2 regulates microglial function. Traffic. 2016;17:1286–96.

    CAS  PubMed  Google Scholar 

  89. Yuan P, Condello C, Keene CD, Wang Y, Bird TD, Paul SM, et al. TREM2 haplo-deficiency in mice and humans impairs the microglia barrier function leading to decreased amyloid compaction and severe axonal dystrophy. Neuron. 2016;92:252–64.

    CAS  PubMed  Google Scholar 

  90. Bemiller SM, McCray TJ, Allan K, Formica SV, Xu G, Wilson G, et al. TREM2 deficiency exacerbates tau pathology through dysregulated kinase signaling in a mouse model of tauopathy. Mol Neurodegener. 2017;12:74.

    PubMed  PubMed Central  Google Scholar 

  91. Leyns CEG, Ulrich JD, Finn MB, Stewart FR, Koscal LJ, Remolina Serrano J, et al. TREM2 deficiency attenuates neuroinflammation and protects against neurodegeneration in a mouse model of tauopathy. Proc Natl Acad Sci USA. 2017;114:11524–9.

    CAS  PubMed  Google Scholar 

  92. Ringe D, Petsko GA. What are pharmacological chaperones and why are they interesting? J Biol. 2009;9:80.

    Google Scholar 

  93. Oh M, Lee JH, Wang W, et al. Potential pharmacological chaperones targeting cancer-associated MCL-1 and Parkinson disease-associated α-synuclein. Proc Natl Acad Sci USA. 2014;111:11007–12.

    CAS  PubMed  Google Scholar 

  94. Mecozzi VJ, Berman DE, Simoes S, Vetanovetz C, Awal MR, Patel VM, et al. Pharmacological chaperones stabilize retromer to limit APP processing. Nat Chem Biol. 2014;10:443–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Zavodszky E, Seaman MN, Moreau K, Jimenez-Sanchez M, Breusegem SY, Harbour ME, Rubinsztein DC. Mutation in VPS35 associated with Parkinson's disease impairs WASH complex association and inhibits autophagy. Nat. Commun. 2014; 5: 3828

  96. Rovelet-Lecrux A, Charbonnier C, Wallon D, Nicolas G, Seaman MNJ, Pottier C, et al. De novo deleterious genetic variations target a biological network centered on Aβ peptide in early-onset Alzheimer disease. Molecular Psychiatry. 2015; 20 :1046-1056

    CAS  PubMed  Google Scholar 

  97. Nicolas G, Charbonnier C, Wallon D, Quenez O, Bellenguez C, Grenier-Boley B, et al. SORL1 rare variants: a major risk factor for familial early-onset Alzheimer's disease. Mol Psychiatry. 2016; 21:831-6.

    PubMed  Google Scholar 

  98. Vardarajan BN, Zhang Y, Lee JH, Cheng R, Bohm C, Ghani M, et al. Coding mutations in SORL1 and Alzheimer disease. Ann Neurol. 2015; 77:215-27.

  99. Tammineni P, Jeong YY, Feng T, Aikal D, Cai Q. Impaired axonal retrograde trafficking of the retromer complex augments lysosomal deficits in Alzheimer's disease neurons. Hum Mol Genet. 2017; 26:4352-4366

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Bhalla A, Vetanovetz CP, Morel E, Chamoun Z, Di Paolo G, Small SA. The location and trafficking routes of the neuronal retromer and its role in amyloid precursor protein transport. Neurobiol Dis. 2012; 47:126-34

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Muhammad A, Flores I, Zhang H, Yu R, Staniszewski A, Planel E, et al. Retromer deficiency observed in Alzheimer's disease causes hippocampal dysfunction, neurodegeneration, and Abeta accumulation. Proc Natl Acad Sci U S A. 2008; 105:7327-32

    CAS  Google Scholar 

  102. Feng T, Niu M, Ji C, Gao Y, Wen J, Bu G, et al. SNX15 Regulates Cell Surface Recycling of APP and Aβ Generation. Mol Neurobiol. 2016; 53:3690-3701

    PubMed  PubMed Central  Google Scholar 

  103. Huang TY, Zhao Y, Li X, Wang X, Tseng IC, Thompson R, et al. SNX27 and SORLA Interact to Reduce Amyloidogenic Subcellular Distribution and Processing of Amyloid Precursor Protein. J Neurosci. 2016; 36:7996-8011

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Morabito MV, Berman DE, Schneider RT, Zhang Y, Leibel RL, Small SA. Hyperleucinemia causes hippocampal retromer deficiency linking diabetes to Alzheimer's disease. Neurobiol Dis. 2014; 65:188-92.

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Sullivan CP, Jay AG, Stack EC, Pakaluk M, Wadlinger E, Fine RE, et al. Retromer disruption promotes amyloidogenic APP processing. Neurobiol Dis. 2011; 43:338-45

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

DP is the Scott Richards North Star Charitable Foundation Chair for Alzheimer’s research. The work from the author’s lab presented in this article was in part supported by grants from the National Institute of Health (AG055707 and AG056689).

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  1. Alzheimer’s Center at Temple, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, 191040, USA

    Alana N. Vagnozzi & Domenico Praticò

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Vagnozzi, A.N., Praticò, D. Endosomal sorting and trafficking, the retromer complex and neurodegeneration. Mol Psychiatry 24, 857–868 (2019). https://doi.org/10.1038/s41380-018-0221-3

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  • DOI: https://doi.org/10.1038/s41380-018-0221-3

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