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View Full Page 14080 • The Journal of Neuroscience, October 10, 2012 • 32(41):14080–14086 Symposium Vps10 Family Proteins and the Retromer Complex in Aging-Related Neurodegeneration and Diabetes Rachel F. Lane,1 Peter St George-Hyslop,2,3 Barbara L. Hempstead,4 Scott A. Small,5 Stephen M. Strittmatter,6 and Sam Gandy7,8 1Alzheimer’s Drug Discovery Foundation, New York, New York 10019, 2Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON M5S 3H2 Canada, 3Cambridge Institute for Medical Research and Department of Clinical Neurosciences, University of Cambridge, Cambridge CB2 0XY, United Kingdom, 4Department of Medicine, Weill Cornell Medical College, New York, New York 10065, 5Department of Neurology and the Taub Institute, Columbia University, School of Physicians and Surgeons, New York, New York 10032, 6Cellular Neuroscience, Neurodegeneration and Repair Program, Departments of Neurology and Neurobiology, Yale University School of Medicine, New Haven, Connecticut 06536, 7Departments of Neurology and Psychiatry and the Alzheimer’s Disease Research Center, Mount Sinai School of Medicine, New York New York 10029, and 8James J. Peters Veterans Affairs Medical Center, Bronx, New York 10468 Members of the vacuolar protein sorting 10 (Vps10) family of receptors (including sortilin, SorL1, SorCS1, SorCS2, and SorCS3) play pleiotropic functions in protein trafficking and intracellular and intercellular signaling in neuronal and non-neuronal cells. Interactions have been documented between Vps10 family members and the retromer coat complex, a key component of the intracellular trafficking apparatus that sorts cargo from the early endosome to the trans-Golgi network. In recent years, genes encoding several members of the Vps10 family of proteins, as well as components of the retromer coat complex, have been implicated as genetic risk factors for sporadic and autosomal dominant forms of neurodegenerative diseases, including Alzheimer’s disease, frontotemporal lobar degeneration, and Parkinson’s disease, with risk for type 2 diabetes mellitus and atherosclerosis. In addition to their functions in protein trafficking, the Vps10 family proteins modulate neurotrophic signaling pathways. Sortilin can impact the intracellular response to brain-derived neu- rotrophic factor (BDNF) by regulating anterograde trafficking of Trk receptors to the synapse and direct control of BDNF levels, while both sortilin and SorCS2 function as cell surface receptors to mediate acute responses to proneurotrophins. This mini-review and symposium will highlight the emerging data from this rapidly growing area of research implicating the Vps10 family of receptors and the retromer in physiological intracellular trafficking signaling by neurotrophins and in the pathogenesis of neurodegeneration. Introduction ponents of the retromer (VPS35 and VPS26) that regulate endo- A number of neurodegenerative diseases including Alzheimer’s somal sorting as risk factors for neurodegenerative diseases. disease (AD), Parkinson’s disease (PD) and frontotemporal lobar SORL1, SORCS1 and VPS35 have been linked to AD (Small et al., degeneration (FTLD, or, simply FTD) are characterized by the 2005; Rogaeva et al., 2007; Liang et al., 2009; Lane et al., 2010; Will- misprocessing and missorting of intracellular proteins [amyloid now et al., 2010; Reitz et al., 2011c;), VPS35 has additionally been precursor protein (APP), ␣-synuclein, tau] within endosomal- linked to PD (Vilarin˜o-Gu¨ell et al., 2011; Zimprich et al., 2011), and lysosomal pathways. Dysfunction within these pathways is pro- SORT1 (sortilin) has been linked to FTD (Carrasquillo et al., 2010; posed to be a major contributing factor to disease progression. Hu et al., 2010). Interestingly, SORCS1 and VPS26a have also been Recently, a number of genome-wide association studies (GWAS) linked to type 2 diabetes mellitus (T2DM) (Goodarzi et al., 2007; and biochemical studies have identified members of the vacuo- Kooner et al., 2011) and SORT1 has been linked to cardiovascular lar protein sorting-10 (Vps10) family of receptors (including disease (CVD) (Musunuru et al., 2010), both independent risk fac- SORT1, SORL1, SORCS1, SORCS2 and SORCS3) and core com- tors for late-onset AD. In addition to their regulation of retrograde trafficking, the Vps10 family members have been implicated in neu- rotrophin signaling through anterograde trafficking of Trk receptors Received July 13, 2012; revised Sept. 4, 2012; accepted Sept. 6, 2012. (Vaegter et al., 2011), the primary receptors for brain-derived neu- We gratefully acknowledge the support of the NIH (NS075685 to S.G., NS030687 to B.L.H., AG025161 to S.A.S., rotrophic factor (BDNF) signaling as well as in regulation of BDNF NS074319 and AG034924 to S.M.S.), the Wellcome Trust, Canadian Institutes of Health Research, Alzheimer Society levels (Chen et al., 2005; Evans et al., 2011) and proneurotrophin of Ontario, and Howard Hughes Medical Institute (P.StG.-H.), the Cure Alzheimer’s Fund (S.G.), and the US Depart- ment of Veteran Affairs (S.G.). R.F.L. and S.G. thank Dr. Alan Attie for providing advice and helpful conversations signaling (Deinhardt et al., 2011). during the preparation of this paper. The VPS10 receptor family also interacts with APOE (APOE Correspondence should be addressed to either of the following: Rachel F. Lane, Alzheimer’s Drug Discovery gene; apoE, protein), a well characterized risk factor for late-onset Foundation, 57 W 57th Street, Suite 904, New York, NY, 10019, E-mail: [email protected], or Sam Gandy, AD (LOAD) and CVD. SorL1 was first identified as a receptor for Departments of Neurology and Psychiatry and the Alzheimer’s Disease Research Center, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York NY 10029, E-mail: [email protected]. apoE in the brain and has subsequently, together with sortilin, DOI:10.1523/JNEUROSCI.3359-12.2012 been implicated in systemic lipoprotein metabolism and as risk Copyright © 2012 the authors 0270-6474/12/3214080-07$15.00/0 factors for CVD (for review, see Willnow et al., 2011). GWAS Lane et al. • Vps10 Receptors in Neurodegeneration J. Neurosci., October 10, 2012 • 32(41):14080–14086 • 14081 Figure 1. APP trafficking and processing. 1, Upon exit from the TGN, APP is sorted into either constitutive secretory vesicles to the plasma membrane or into clathrin-coated vesicles into the endosomal pathway dependent on AP4. Within the secretory pathway and primarily at the plasma membrane (PM), APP is cleaved by the ␣-secretases (ADAM10, ADAM17) into the soluble APP␣ (sAPP␣) fragment and a membrane-bound ␣CTF. The ␣CTF is subsequently cleaved by the ␥-secretase machinery resulting in generation of the p3 fragment and the APP intracellular domain (AICD). 2, Following residence at the PM, some unprocessed APP escapes ␣-secretase cleavage and is internalized into the endosomal pathway. Within low pH endosomal compartments, APP is cleaved by BACE, resulting in generation of sAPP␤ and the ␤CTF. Cleavage of the ␤CTF by ␥-secretase occurs initially at the ␧-site. This is subsequently followed by additional C-terminal cleavage eventstothe␥-secretasesite(Nterminaltothe␧-site)resultinginformationoftheA␤peptide(ofvaryinglengths)andtheAICD.3,4,APPisrecycledfromtheearlyendosomalcompartments[early endosomes (EE), late endosomes (LE), recycling endosomes (RE)] to the TGN via the retromer complex and its receptors, the Vps10 family members. To date, SorL1 has been shown to regulate APP exitfromEEandsortingfromEEtotheTGNviaaninteractionwithcorecomponentsoftheretromer.Whiletheretromerhasbeenadditionallyimplicatedinretrogradetraffickingbetweenrecycling endosomes and the TGN, direct evidence has not yet been provided for this compartment in retromer regulation of APP trafficking. Evidence suggests SorCS1 trafficking within endosomal compartments is dependent on SorL1 and the retromer (4). support the interaction of APOE and VPS10 family members in risk amyloid ␤ (A␤). The acidic nature of the endosomal compart- for AD and CVD, in part based on data suggesting that SORCS1 and ments promotes production and aggregation of A␤ (for review, APOE interact in the development of AD (Wang et al., 2012). see Small and Gandy, 2006), and dysfunction within the endo- SORCS1 was also highlighted in GWAS for T2DM (Goodarzi et al., somal pathway is implicated early in disease progression (Cataldo 2007) as was the retromer component, Vps26a (Kooner et al., 2011). et al., 1997, 2000, 2004). Activity of BACE1, the ␤-site APP cleav- CVD and T2DM are established risk factors for LOAD, and elucida- age enzyme, is optimized within acidic environments and is the tion of the biology of Vps10 family of receptors may shed light on initial APP cleavage event in the amyloidogenic cascade that re- molecular mechanisms linking these common systemic metabolic sults in the production of A␤ (Fig. 1; for review, see Small and diseases with equally common neurodegenerative diseases. Since Gandy, 2006). Proteins that modulate internalization of APP and much of the attention recently drawn to this family of proteins has APP C-terminal fragments (CTFs) into and between endosomal resulted from their linkage to neurological diseases, we will begin this compartments and from endosome to lysosome remain to be mini-review and symposium with highlights of Vps10 family-based fully characterized. In the last few years, however, in the last few and retromer-based pathogenesis before turning to a discussion of years, a number of studies have provided evidence
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