VPS35: Difference between revisions

'''Vacuolar protein sorting ortholog 35 (VPS35)''' is a [[protein]] involved in [[autophagy]] and is implicated in [[Neurodegeneration|neurodegenerative]] diseases, such as [[Parkinson's disease]] (PD) and [[Alzheimer's disease]] (AD).<ref name="Reitz_2015">{{cite journal | vauthors = Reitz C | title = The role of the retromer complex in aging-related neurodegeneration: a molecular and genomic review | journal = Molecular Genetics and Genomics | volume = 290 | issue = 2 | pages = 413–27 | date = April 2015 | pmid = 25332075 | pmc = 4363161 | doi = 10.1007/s00438-014-0939-9 }}</ref><ref name="Reitz_2018">{{cite journal | vauthors = Reitz C | title = Retromer Dysfunction and Neurodegenerative Disease | journal = Current Genomics | volume = 19 | issue = 4 | pages = 279–288 | date = May 2018 | pmid = 29755290 | doi = 10.2174/1389202919666171024122809 | pmc = 5930449 }}</ref><ref name="Brodin_2018">{{cite journal | vauthors = Brodin L, Shupliakov O | title = Retromer in Synaptic Function and Pathology | language = en | journal = Frontiers in Synaptic Neuroscience | volume = 10 | pages = 37 | date = 2018 | pmid = 30405388 | doi = 10.3389/fnsyn.2018.00037 | pmc = 6207580 | doi-access = free }}</ref><ref name="Follett_2017">{{cite journal | vauthors = Follett J, Bugarcic A, Collins BM, Teasdale RD | title = Retromer's Role in Endosomal Trafficking and Impaired Function in Neurodegenerative Diseases | journal = Current Protein & Peptide Science | volume = 18 | issue = 7 | pages = 687–701 | date = 2017-07-01 | pmid = 26965691 | doi = 10.2174/1389203717666160311121246 }}</ref><ref name="Trousdale_2015">{{cite journal | vauthors = Trousdale C, Kim K | title = Retromer: Structure, function, and roles in mammalian disease | journal = European Journal of Cell Biology | volume = 94 | issue = 11 | pages = 513–21 | date = November 2015 | pmid = 26220253 | doi = 10.1016/j.ejcb.2015.07.002 }}</ref> VPS35 is part of a complex called the [[retromer]], which is responsible for transporting select cargo proteins between vesicular structures (e.g., [[endosome]]s, [[lysosome]]s, [[vacuole]]s) and the [[Golgi apparatus]].<ref name="Reitz_2015" /><ref name="Vagnozzi_2019">{{cite journal | vauthors = Vagnozzi AN, Li JG, Chiu J, Razmpour R, Warfield R, Ramirez SH, Praticò D | title = VPS35 regulates tau phosphorylation and neuropathology in tauopathy | journal = Molecular Psychiatry | date = July 2019 | volume = 26 | issue = 11 | pages = 6992–7005 | pmid = 31289348 | pmc = 6949432 | doi = 10.1038/s41380-019-0453-x }}{{Retracted|doi=10.1038/s41380-023-01973-9|pmid=36697754}}</ref><ref name="Rahman_2019">{{cite journal | vauthors = Rahman AA, Morrison BE | title = Contributions of VPS35 Mutations to Parkinson's Disease | journal = Neuroscience | volume = 401 | pages = 1–10 | date = March 2019 | pmid = 30660673 | doi = 10.1016/j.neuroscience.2019.01.006 | pmc = 6422337 }}</ref><ref name="Vilariño-Güell_2011">{{cite journal | vauthors = Vilariño-Güell C, Wider C, Ross OA, Dachsel JC, Kachergus JM, Lincoln SJ, Soto-Ortolaza AI, Cobb SA, Wilhoite GJ, Bacon JA, Behrouz B, Melrose HL, Hentati E, Puschmann A, Evans DM, Conibear E, Wasserman WW, Aasly JO, Burkhard PR, Djaldetti R, Ghika J, Hentati F, Krygowska-Wajs A, Lynch T, Melamed E, Rajput A, Rajput AH, Solida A, Wu RM, Uitti RJ, Wszolek ZK, Vingerhoets F, Farrer MJ | display-authors = 6 | title = VPS35 mutations in Parkinson disease | journal = American Journal of Human Genetics | volume = 89 | issue = 1 | pages = 162–7 | date = July 2011 | pmid = 21763482 | doi = 10.1016/j.ajhg.2011.06.001 | pmc = 3135796 }}</ref><ref name="Williams_2017">{{cite journal | vauthors = Williams ET, Chen X, Moore DJ | title = VPS35, the Retromer Complex and Parkinson's Disease | journal = Journal of Parkinson's Disease | volume = 7 | issue = 2 | pages = 219–233 | date = 2017-01-01 | pmid = 28222538 | doi = 10.3233/JPD-161020 | pmc = 5438477 }}</ref> Mutations in the VPS35 [[gene]] (''VPS35'') cause aberrant autophagy, where cargo proteins fail to be transported and dysfunctional or unnecessary proteins fail to be degraded.<ref name="Trousdale_2015" /><ref name="Rahman_2019" /> There are numerous pathways affected by altered ''VPS35'' levels and activity, which have clinical significance in neurodegeneration.<ref name="Reitz_2015" /><ref name="Reitz_2018" /><ref name="Brodin_2018" /><ref name="Follett_2017" /><ref name="Trousdale_2015" /> There is therapeutic relevance for VPS35, as interventions aimed at correcting VPS35 function are in speculation.<ref name="Trousdale_2015" /><ref name="Cutillo_2020">{{cite journal | vauthors = Cutillo G, Simon DK, Eleuteri S | title = VPS35 and the mitochondria: Connecting the dots in Parkinson's disease pathophysiology | journal = Neurobiology of Disease | volume = 145 | pages = 105056 | date = November 2020 | pmid = 32853677 | doi = 10.1016/j.nbd.2020.105056 | s2cid = 221277514 | doi-access = free }}</ref><ref name="Eleuteri_2019">{{cite journal | vauthors = Eleuteri S, Albanese A | title = VPS35-Based Approach: A Potential Innovative Treatment in Parkinson's Disease | journal = Frontiers in Neurology | volume = 10 | pages = 1272 | date = 2019-12-17 | pmid = 31920908 | pmc = 6928206 | doi = 10.3389/fneur.2019.01272 | doi-access = free }}</ref>{{Infobox_gene}}

In humans, ''VPS35'' is [[Transcription (biology)|transcribed]] on [[chromosome]] 16q11.2 where is spans about 29.6 [[kilobase]]s and contains 17 [[exon]]s.<ref name="Cutillo_2020" /><ref name="Eleuteri_2019" /><ref name="Deng_2013">{{cite journal | vauthors = Deng H, Gao K, Jankovic J | title = The VPS35 gene and Parkinson's disease | journal = Movement Disorders | volume = 28 | issue = 5 | pages = 569–75 | date = May 2013 | pmid = 23536430 | doi = 10.1002/mds.25430 | s2cid = 16641707 }}</ref><ref name="Sassone_2020">{{cite journal | vauthors = Sassone J, Reale C, Dati G, Regoni M, Pellecchia MT, Garavaglia B | title = The Role of VPS35 in the Pathobiology of Parkinson's Disease | journal = Cellular and Molecular Neurobiology | date = April 2020 | volume = 41 | issue = 2 | pages = 199–227 | pmid = 32323152 | doi = 10.1007/s10571-020-00849-8 | s2cid = 216076582 }}</ref> It is [[Conserved sequence|evolutionarily conserved]] and required for survival, as mouse [[knockout studies]] have demonstrated embryonic lethality.<ref name="Reitz_2018" /><ref name="Brodin_2018" /><ref name="Vagnozzi_2019" /><ref name="Vilariño-Güell_2011" /><ref name="Williams_2017" /><ref name="Cutillo_2020" /><ref name="Eleuteri_2019" /> ''VPS35'' levels peak at postnatal days 10-15 and then decline to a low, stable level throughout adulthood.<ref name="Brodin_2018" /> [[RNA]] expression of ''VPS35'' is ubiquitous throughout the body, but are higher in the [[brain]], [[heart]], [[gonad]]s, [[spleen]], and [[skeletal muscle]], and lower in the [[lung]], [[liver]], [[kidney]], and blood [[leukocytes]].<ref name="Deng_2013" /><ref name="Sassone_2020" />[[File:Cargo_recognition_complex_crystal_structure.png|left|thumb|298x298px|Crystal structure of the cargo recognition complex. VPS26 (yellow), VPS35 (light blue), and VPS29 (light purple) form a trimer. VPS35 is bound by VPS26 at its N-terminus and by VPS29 at its C-terminus.]]

VPS35 binds with other proteins to form the retromer, an evolutionarily conserved complex that plays a major role in [[transmembrane protein]] recycling from endosomes to the ''trans''-Golgi network ([[Golgi apparatus|TGN]]).<ref name="Reitz_2015" /><ref name="Vagnozzi_2019" /><ref name="Rahman_2019" /><ref name="Vilariño-Güell_2011" /><ref name="Williams_2017" /> VPS35 itself folds into a secondary structure that represents an α-helical [[solenoid]], containing 34 [[Alpha helix|α-helix]] repeats.<ref name="Sassone_2020" />

As part of the retromer, VPS35 [[trimerize]]s with other vacuolar protein sorting orthologs, VPS26 and VPS29. In less common situations, VPS35 can bind VPS26 and VPS29 alone, creating [[heterodimers]].<ref name="Trousdale_2015" /> VPS26 binds the [[N-terminus]] of VPS35 at a conserved PRLYL motif (residues 1-172), whereas a [[C-terminus|C-terminal]] α-solenoid fold (residues 307-796) binds VPS29.<ref name="Reitz_2015" /><ref name="Deng_2013" /><ref name="Sassone_2020" /> These VPS orthologs stabilize each other within the retromer; VPS35 knockdown can lead to VPS29 degradation, and vice versa.<ref name="Trousdale_2015" /><ref name="Rahman_2019" /> The VPS35, VPS26, and VPS29 trimer forms the cargo recognition complex, a necessary component for the retromer's ability to regulate vesicular sorting.<ref name="Reitz_2015" /><ref name="Reitz_2018" /><ref name="Brodin_2018" /><ref name="Trousdale_2015" /><ref name="Vagnozzi_2019" /><ref name="Rahman_2019" /><ref name="Vilariño-Güell_2011" /><ref name="Williams_2017" /><ref name="Cutillo_2020" /><ref name="Vergés_2016">{{cite journal | vauthors = Vergés M | title = Retromer in Polarized Protein Transport | journal = International Review of Cell and Molecular Biology | volume = 323 | pages = 129–79 | date = 2016-01-01 | pmid = 26944621 | doi = 10.1016/bs.ircmb.2015.12.005 | publisher = Academic Press | isbn = 9780128048085 | veditors = Jeon KW }}</ref> This is achieved by specifically targeting [[sorting nexin]]s (i.e., SNX1, SNX2, SNX5, SNX6, and SNX32), which anchor the retromer to endosomes and other vesicular structures.<ref name="Brodin_2018" /><ref name="Eleuteri_2019" /><ref name="Sassone_2020" /><ref name="Vergés_2016" />

Clinically, low expression of ''VPS35'' in the brain is a risk factor of AD, since it is known that regions high in AD pathology show low VPS35 activity.<ref name="Trousdale_2015" /><ref name="Vagnozzi_2019" /><ref name="Rahman_2019" /><ref>{{cite journal | vauthors = Qureshi YH, Baez P, Reitz C | title = Endosomal Trafficking in Alzheimer's Disease, Parkinson's Disease, and Neuronal Ceroid Lipofuscinosis | journal = Molecular and Cellular Biology | volume = 40 | issue = 19 | date = September 2020 | pmid = 32690545 | doi = 10.1128/MCB.00262-20 | pmc = 7491951 }}</ref> Specifically, there are decreased levels of ''VPS35'' in the [[Hippocampus|hippocampi]] of [[postmortem]] AD patients relative to healthy patients.<ref name="Reitz_2018" /><ref name="Rahman_2019" /><ref name="Vilariño-Güell_2011" /><ref name="Deng_2013" /> This can be modeled in a specific strain of AD-like mice, Tg2576, whereby [[heterozygous]] deletion of ''VPS35'' enhances AD phenotypes in the hippocampus and [[Cortex (anatomy)|cortex]].<ref name="Williams_2017" /> Humans possessing a VPS35 genetic variant also increases the risk of developing AD.<ref name="Vilariño-Güell_2011" /> Consequently, AD pathology is linked to aberrant retromer function.<ref name="Eleuteri_2019" />

VPS35 knockdown studies have demonstrated increased amyloid precursor protein ([[Amyloid precursor protein|APP]]) and Aβ plaque levels, hallmarks of AD.<ref name="Brodin_2018" /> VPS35 insufficiency reduces transport of endosomes containing APP, ultimately facilitating APP aggregation and formation of Aβ plaques.<ref name="Reitz_2015" /><ref name="Trousdale_2015" /><ref name="Eleuteri_2019" /> [[SORL1|Sortilin-related receptor]] is a cargo protein that interacts with VPS35; it binds APP and delivers APP to the lysosomal system for degradation.<ref name="Vagnozzi_2019" />{{cn}} Impairment of retromer activity by ''VPS35'' mutation also increases beta-secretase 1 ([[Beta-secretase 1|BACE1]]) activity, which cleaves larger APPs and enhances Aβ plaque toxicity.<ref name="Reitz_2018" /><ref name="Brodin_2018" /> This is observed in heterozygous mice deficient in VPS35, which have greater amounts of Aβ40 and Aβ42 compared to controls.<ref name="Reitz_2015" /> Decreased expression of ''VPS35'' in Drosophila AD models further shows an increase in Aβ plaque formation, BACE1 activity, memory deficits, and synaptic dysfunction.<ref name="Vagnozzi_2019" /><ref name="Rahman_2019" /><ref name="Deng_2013" />