Retromer is a protein assembly that has a central role in endosomal trafficking, and retromer dysfunction has been linked to a growing number of neurological disorders. First linked to Alzheimer disease, retromer dysfunction causes a range of pathophysiological consequences that have been shown to contribute to the core pathological features of the disease. Genetic studies have established that retromer dysfunction is also pathogenically linked to Parkinson disease, although the biological mechanisms that mediate this link are only now being elucidated. Most recently, studies have shown that retromer is a tractable target in drug discovery for these and other disorders of the nervous system.
This is a preview of subscription content, access via your institution
Open Access articles citing this article.
Microglial VPS35 deficiency impairs Aβ phagocytosis and Aβ-induced disease-associated microglia, and enhances Aβ associated pathology
Journal of Neuroinflammation Open Access 02 March 2022
Future Journal of Pharmaceutical Sciences Open Access 16 March 2021
Oncogene Open Access 08 January 2021
Subscribe to Journal
Get full journal access for 1 year
only $8.25 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
Schekman, R. Charting the secretory pathway in a simple eukaryote. Mol. Biol. Cell 21, 3781–3784 (2010).
Henne, W. M., Buchkovich, N. J. & Emr, S. D. The ESCRT pathway. Dev. Cell 21, 77–91 (2011).
Seaman, M. N., McCaffery, J. M. & Emr, S. D. A membrane coat complex essential for endosome-to-Golgi retrograde transport in yeast. J. Cell Biol. 142, 665–681 (1998).
Haft, C. R. et al. Human orthologs of yeast vacuolar protein sorting proteins Vps26, 29, and 35: assembly into multimeric complexes. Mol. Biol. Cell 11, 4105–4116 (2000).
Seaman, M. N. Cargo-selective endosomal sorting for retrieval to the Golgi requires retromer. J. Cell Biol. 165, 111–122 (2004).
Arighi, C. N., Hartnell, L. M., Aguilar, R. C., Haft, C. R. & Bonifacino, J. S. Role of the mammalian retromer in sorting of the cation-independent mannose 6-phosphate receptor. J. Cell Biol. 165, 123–133 (2004).
Small, S. A. et al. Model-guided microarray implicates the retromer complex in Alzheimer's disease. Ann. Neurol. 58, 909–919 (2005).
Burd, C. & Cullen, P. J. Retromer: a master conductor of endosome sorting. Cold Spring Harb. Perspect. Biol. 6, a016774 (2014).
Carroll, R. C., Beattie, E. C., von Zastrow, M. & Malenka, R. C. Role of AMPA receptor endocytosis in synaptic plasticity. Nature Rev. Neurosci. 2, 315–324 (2001).
Choy, R. W. et al. Retromer mediates a discrete route of local membrane delivery to dendrites. Neuron 82, 55–62 (2014).
Zhang, D. et al. RAB-6.2 and the retromer regulate glutamate receptor recycling through a retrograde pathway. J. Cell Biol. 196, 85–101 (2012).
Hussain, N. K., Diering, G. H., Sole, J., Anggono, V. & Huganir, R. L. Sorting nexin 27 regulates basal and activity-dependent trafficking of AMPARs. Proc. Natl Acad. Sci. USA 111, 11840–11845 (2014).
Loo, L. S., Tang, N., Al-Haddawi, M., Dawe, G. S. & Hong, W. A role for sorting nexin 27 in AMPA receptor trafficking. Nature Commun. 5, 3176 (2014).
Feinstein, T. N. et al. Retromer terminates the generation of cAMP by internalized PTH receptors. Nature Chem. Biol. 7, 278–284 (2011).
Temkin, P. et al. SNX27 mediates retromer tubule entry and endosome-to-plasma membrane trafficking of signalling receptors. Nature Cell Biol. 13, 715–721 (2011).
Seaman, M. N. Recycle your receptors with retromer. Trends Cell Biol. 15, 68–75 (2005).
Kerr, M. C. et al. A novel mammalian retromer component, Vps26B. Traffic 6, 991–1001 (2005).
Collins, B. M. et al. Structure of Vps26B and mapping of its interaction with the retromer protein complex. Traffic 9, 366–379 (2008).
Kim, E. et al. Identification of novel retromer complexes in the mouse testis. Biochem. Biophys. Res. Commun. 375, 16–21 (2008).
Bugarcic, A. et al. Vps26A and Vps26B subunits define distinct retromer complexes. Traffic 12, 1759–1773 (2011).
Gallon, M. et al. A unique PDZ domain and arrestin-like fold interaction reveals mechanistic details of endocytic recycling by SNX27–retromer. Proc. Natl Acad. Sci. USA 111, E3604–E3613 (2014).
Kim, E. et al. Implication of mouse Vps26b–Vps29–Vps35 retromer complex in sortilin trafficking. Biochem. Biophys. Res. Commun. 403, 167–171 (2010).
Attar, N. & Cullen, P. J. The retromer complex. Adv. Enzyme Regul. 50, 216–236 (2010).
Rojas, R., Kametaka, S., Haft, C. R. & Bonifacino, J. S. Interchangeable but essential functions of SNX1 and SNX2 in the association of retromer with endosomes and the trafficking of mannose 6-phosphate receptors. Mol. Cell. Biol. 27, 1112–1124 (2007).
Wassmer, T. et al. A loss-of-function screen reveals SNX5 and SNX6 as potential components of the mammalian retromer. J. Cell Sci. 120, 45–54 (2007).
Sierecki, E. et al. Rapid mapping of interactions between human SNX–BAR proteins measured in vitro by AlphaScreen and single-molecule spectroscopy. Mol. Cell. Proteom. 13, 2233–2245 (2014).
van Weering, J. R. et al. Molecular basis for SNX–BAR-mediated assembly of distinct endosomal sorting tubules. EMBO J. 31, 4466–4480 (2012).
Harbour, M. E. et al. The cargo-selective retromer complex is a recruiting hub for protein complexes that regulate endosomal tubule dynamics. J. Cell Sci. 123, 3703–3717 (2010).
Harterink, M. et al. A SNX3-dependent retromer pathway mediates retrograde transport of the Wnt sorting receptor Wntless and is required for Wnt secretion. Nature Cell Biol. 13, 914–923 (2011).
Rojas, R. et al. Regulation of retromer recruitment to endosomes by sequential action of Rab5 and Rab7. J. Cell Biol. 183, 513–526 (2008).
Seaman, M. N., Harbour, M. E., Tattersall, D., Read, E. & Bright, N. Membrane recruitment of the cargo-selective retromer subcomplex is catalysed by the small GTPase Rab7 and inhibited by the Rab–GAP TBC1D5. J. Cell Sci. 122, 2371–2382 (2009).
Harrison, M. S. et al. A mechanism for retromer endosomal coat complex assembly with cargo. Proc. Natl Acad. Sci. USA 111, 267–272 (2014).
Cozier, G. E. et al. The phox homology (PX) domain-dependent, 3-phosphoinositide-mediated association of sorting nexin-1 with an early sorting endosomal compartment is required for its ability to regulate epidermal growth factor receptor degradation. J. Biol. Chem. 277, 48730–48736 (2002).
Steinberg, F. et al. A global analysis of SNX27–retromer assembly and cargo specificity reveals a function in glucose and metal ion transport. Nature Cell Biol. 15, 461–471 (2013).
Derivery, E. & Gautreau, A. Evolutionary conservation of the WASH complex, an actin polymerization machine involved in endosomal fission. Commun. Integr. Biol. 3, 227–230 (2010).
Gomez, T. S. & Billadeau, D. D. A FAM21-containing WASH complex regulates retromer-dependent sorting. Dev. Cell 17, 699–711 (2009).
Lucin, K. M. et al. Microglial beclin 1 regulates retromer trafficking and phagocytosis and is impaired in Alzheimer's disease. Neuron 79, 873–886 (2013).
Rogaeva, E. et al. The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease. Nature Genet. 39, 168–177 (2007).
Muhammad, A. et al. Retromer deficiency observed in Alzheimer's disease causes hippocampal dysfunction, neurodegeneration, and Aβ accumulation. Proc. Natl Acad. Sci. USA 105, 7327–7332 (2008).
Bhalla, A. et al. The location and trafficking routes of the neuronal retromer and its role in amyloid precursor protein transport. Neurobiol. Dis. 47, 126–134 (2012).
Fjorback, A. W. et al. Retromer binds the FANSHY sorting motif in SorLA to regulate amyloid precursor protein sorting and processing. J. Neurosci. 32, 1467–1480 (2012).
Lane, R. F. et al. Vps10 family proteins and the retromer complex in aging-related neurodegeneration and diabetes. J. Neurosci. 32, 14080–14086 (2012).
Small, S. A. & Gandy, S. Sorting through the cell biology of Alzheimer's disease: intracellular pathways to pathogenesis. Neuron 52, 15–31 (2006).
Canuel, M., Korkidakis, A., Konnyu, K. & Morales, C. R. Sortilin mediates the lysosomal targeting of cathepsins D and H. Biochem. Biophys. Res. Commun. 373, 292–297 (2008).
Futerman, A. H. & van Meer, G. The cell biology of lysosomal storage disorders. Nature Rev. Mol. Cell Biol. 5, 554–565 (2004).
Zavodszky, E. et al. Mutation in VPS35 associated with Parkinson's disease impairs WASH complex association and inhibits autophagy. Nature Commun. 5, 3828 (2014).
Nixon, R. A. The role of autophagy in neurodegenerative disease. Nature Med. 19, 983–997 (2013).
Dhungel, R. et al. Parkinson's disease genes VPS35 and EIF4G1 interact genetically and converge on α-synuclein. Neuron 85, 76–87 (2015).
Walker, L. C., Diamond, M. I., Duff, K. E. & Hyman, B. T. Mechanisms of protein seeding in neurodegenerative diseases. JAMA Neurol. 70, 304–310 (2013).
Luk, K. C. et al. Pathological α-synuclein transmission initiates Parkinson-like neurodegeneration in nontransgenic mice. Science 338, 949–953 (2012).
Small, S. A. Isolating pathogenic mechanisms embedded within the hippocampal circuit through regional vulnerability. Neuron 84, 32–39 (2014).
Moreno, H. et al. Imaging the Aβ-related neurotoxicity of Alzheimer disease. Arch. Neurol. 64, 1467–1477 (2007).
Dodson, S. E. et al. LR11/SorLA expression is reduced in sporadic Alzheimer disease but not in familial Alzheimer disease. J. Neuropathol. Exp. Neurol. 65, 866–872 (2006).
Lambert, J. C. et al. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease. Nature Genet. 45, 1452–1458 (2013).
Vardarajan, B. N. et al. Identification of Alzheimer disease-associated variants in genes that regulate retromer function. Neurobiol. Aging 33, 2231.e15–2231.e30 (2012).
Reitz, C. et al. Independent and epistatic effects of variants in VPS10-d receptors on Alzheimer disease risk and processing of the amyloid precursor protein (APP). Transl Psychiatry 3, e256 (2013).
Morel, E. et al. Phosphatidylinositol-3-phosphate regulates sorting and processing of amyloid precursor protein through the endosomal system. Nature Commun. 4, 2250 (2013).
Wen, L. et al. VPS35 haploinsufficiency increases Alzheimer's disease neuropathology. J. Cell Biol. 195, 765–779 (2011).
Lane, R. F. et al. Diabetes-associated SorCS1 regulates Alzheimer's amyloid-β metabolism: evidence for involvement of SorL1 and the retromer complex. J. Neurosci. 30, 13110–13115 (2010).
Vieira, S. I. et al. Retrieval of the Alzheimer's amyloid precursor protein from the endosome to the TGN is S655 phosphorylation state-dependent and retromer-mediated. Mol. Neurodegener. 5, 40 (2010).
Mecozzi, V. J. et al. Pharmacological chaperones stabilize retromer to limit APP processing. Nature Chem. Biol. 10, 443–449 (2014).
Choy, R. W., Cheng, Z. & Schekman, R. Amyloid precursor protein (APP) traffics from the cell surface via endosomes for amyloid β (Aβ) production in the trans-Golgi network. Proc. Natl Acad. Sci. USA 109, E2077–E2082 (2012).
Guerreiro, R. et al. TREM2 variants in Alzheimer's disease. N. Engl. J. Med. 368, 117–127 (2013).
Kleinberger, G. et al. TREM2 mutations implicated in neurodegeneration impair cell surface transport and phagocytosis. Sci. Transl Med. 6, 243ra286 (2014).
Mosher, K. I. & Wyss-Coray, T. Microglial dysfunction in brain aging and Alzheimer's disease. Biochem. Pharmacol. 88, 594–604 (2014).
Wu, J. W. et al. Small misfolded tau species are internalized via bulk endocytosis and anterogradely and retrogradely transported in neurons. J. Biol. Chem. 288, 1856–1870 (2013).
Michel, C. H. et al. Extracellular monomeric tau protein is sufficient to initiate the spread of tau protein pathology. J. Biol. Chem. 289, 956–967 (2014).
Khurana, V. et al. Lysosomal dysfunction promotes cleavage and neurotoxicity of tau in vivo. PLoS Genet. 6, e1001026 (2010).
Zimprich, A. et al. A mutation in VPS35, encoding a subunit of the retromer complex, causes late-onset Parkinson disease. Am. J. Hum. Genet. 89, 168–175 (2011).
Vilarino-Guell, C. et al. VPS35 mutations in Parkinson disease. Am. J. Hum. Genet. 89, 162–167 (2011).
Macleod, D. A. et al. RAB7L1 interacts with LRRK2 to modify intraneuronal protein sorting and Parkinson's disease risk. Neuron 77, 425–439 (2013).
Bi, F., Li, F., Huang, C. & Zhou, H. Pathogenic mutation in VPS35 impairs its protection against MPP+ cytotoxicity. Int. J. Biol. Sci. 9, 149–155 (2013).
Follett, J. et al. The Vps35 D620N mutation linked to Parkinson's disease disrupts the cargo sorting function of retromer. Traffic 15, 230–244 (2014).
Linhart, R. 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. 9, 23 (2014).
McGough, I. J. et al. Retromer binding to FAM21 and the WASH complex is perturbed by the Parkinson disease-linked VPS35(D620N) mutation. Curr. Biol. 24, 1670–1676 (2014).
Miura, E. et al. VPS35 dysfunction impairs lysosomal degradation of α-synuclein and exacerbates neurotoxicity in a Drosophila model of Parkinson's disease. Neurobiol. Dis. 71, 1–13 (2014).
Tsika, E. et al. Parkinson's disease-linked mutations in VPS35 induce dopaminergic neurodegeneration. Hum. Mol. Genet. 23, 4621–4638 (2014).
Dodson, M. W., Leung, L. K., Lone, M., Lizzio, M. A. & Guo, M. Novel ethyl methanesulfonate (EMS)-induced null alleles of the Drosophila homolog of LRRK2 reveal a crucial role in endolysosomal functions and autophagy in vivo. Dis. Model. Mech. 7, 1351–1363 (2014).
Wang, X. et al. Loss of sorting nexin 27 contributes to excitatory synaptic dysfunction by modulating glutamate receptor recycling in Down's syndrome. Nature Med. 19, 473–480 (2013).
Blackstone, C., O'Kane, C. J. & Reid, E. Hereditary spastic paraplegias: membrane traffic and the motor pathway. Nature Rev. Neurosci. 12, 31–42 (2011).
Valdmanis, P. N. et al. Mutations in the KIAA0196 gene at the SPG8 locus cause hereditary spastic paraplegia. Am. J. Hum. Genet. 80, 152–161 (2007).
Jalanko, A. & Braulke, T. Neuronal ceroid lipofuscinoses. Biochim. Biophys. Acta 1793, 697–709 (2009).
Metcalf, D. J., Calvi, A. A., Seaman, M., Mitchison, H. M. & Cutler, D. F. Loss of the Batten disease gene CLN3 prevents exit from the TGN of the mannose 6-phosphate receptor. Traffic 9, 1905–1914 (2008).
Mamo, A., Jules, F., Dumaresq-Doiron, K., Costantino, S. & Lefrancois, S. The role of ceroid lipofuscinosis neuronal protein 5 (CLN5) in endosomal sorting. Mol. Cell. Biol. 32, 1855–1866 (2012).
Verges, M., Sebastian, I. & Mostov, K. E. Phosphoinositide 3-kinase regulates the role of retromer in transcytosis of the polymeric immunoglobulin receptor. Exp. Cell Res. 313, 707–718 (2007).
Garber, K. Neurodegeneration. Potential Alzheimer's drug spurs protein recycling. Science 344, 351 (2014).
Cataldo, A. et al. Endocytic disturbances distinguish among subtypes of Alzheimer's disease and related disorders. Ann. Neurol. 50, 661–665 (2001).
Israel, M. A. et al. Probing sporadic and familial Alzheimer's disease using induced pluripotent stem cells. Nature 482, 216–220 (2012).
Ye, S. et al. Apolipoprotein (apo) E4 enhances amyloid β peptide production in cultured neuronal cells: apoE structure as a potential therapeutic target. Proc. Natl Acad. Sci. USA 102, 18700–18705 (2005).
Yu, J. T., Tan, L. & Hardy, J. Apolipoprotein E in Alzheimer's disease: an update. Ann. Rev. Neurosci. 37, 79–100 (2014).
Nalls, M. A. et al. Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson's disease. Nature Genet. 46, 989–993 (2014).
Khan, U. A. et al. Molecular drivers and cortical spread of lateral entorhinal cortex dysfunction in preclinical Alzheimer's disease. Nature Neurosci. 17, 304–311 (2014).
Small, S. A. Pharmacological chaperones in the age of proteomic pathology. Proc. Natl Acad. Sci. USA 111, 12274–12275 (2014).
The authors thank the US National Institute on Ageing, US National Institutes of Health grants AG025161 and AG08702, The Alzheimer's Association, The McKnight Endowment for Neuroscience, the Ellison Medical Foundation and The Fidelity Biosciences Research Initiative for funding, and give special thanks to S. Weninger for advice and encouragement. The authors also thank G. Di Paolo for discussions regarding the manuscript.
The authors declare no competing financial interests.
About this article
Cite this article
Small, S., Petsko, G. Retromer in Alzheimer disease, Parkinson disease and other neurological disorders. Nat Rev Neurosci 16, 126–132 (2015). https://doi.org/10.1038/nrn3896
This article is cited by
Microglial VPS35 deficiency impairs Aβ phagocytosis and Aβ-induced disease-associated microglia, and enhances Aβ associated pathology
Journal of Neuroinflammation (2022)
Enhanced cleavage of APP by co-expressed Bace1 alters the distribution of APP and its fragments in neuronal and non-neuronal cells
Molecular Neurobiology (2022)
Future Journal of Pharmaceutical Sciences (2021)
Metabolic Brain Disease (2021)