Editing Alpha-synuclein (section)

== Function ==

Although the function of alpha-synuclein is not well understood, studies suggest that it plays a role in restricting the mobility of synaptic vesicles, consequently attenuating [[synaptic vesicle recycling]] and neurotransmitter release.<ref>{{cite journal | vauthors = Larsen KE, Schmitz Y, Troyer MD, Mosharov E, Dietrich P, Quazi AZ, Savalle M, Nemani V, Chaudhry FA, Edwards RH, Stefanis L, Sulzer D | title = Alpha-synuclein overexpression in PC12 and chromaffin cells impairs catecholamine release by interfering with a late step in exocytosis | journal = The Journal of Neuroscience| volume = 26 | issue = 46 | pages = 11915–11922 | date = November 2006 | pmid = 17108165 | pmc = 6674868 | doi = 10.1523/JNEUROSCI.3821-06.2006 }}</ref><ref>{{cite journal | vauthors = Nemani VM, Lu W, Berge V, Nakamura K, Onoa B, Lee MK, Chaudhry FA, Nicoll RA, Edwards RH | title = Increased expression of alpha-synuclein reduces neurotransmitter release by inhibiting synaptic vesicle reclustering after endocytosis | journal = Neuron | volume = 65 | issue = 1 | pages = 66–79 | date = January 2010 | pmid = 20152114 | pmc = 3119527 | doi = 10.1016/j.neuron.2009.12.023 }}</ref><ref>{{cite journal | vauthors = Scott DA, Tabarean I, Tang Y, Cartier A, Masliah E, Roy S | title = A pathologic cascade leading to synaptic dysfunction in alpha-synuclein-induced neurodegeneration | journal = The Journal of Neuroscience| volume = 30 | issue = 24 | pages = 8083–8095 | date = June 2010 | pmid = 20554859 | pmc = 2901533 | doi = 10.1523/JNEUROSCI.1091-10.2010 }}</ref><ref>{{cite journal | vauthors = Scott D, Roy S | title = α-Synuclein inhibits intersynaptic vesicle mobility and maintains recycling-pool homeostasis | journal = The Journal of Neuroscience| volume = 32 | issue = 30 | pages = 10129–10135 | date = July 2012 | pmid = 22836248 | pmc = 3426499 | doi = 10.1523/JNEUROSCI.0535-12.2012 }}</ref><ref>{{cite journal | vauthors = Vargas KJ, Makani S, Davis T, Westphal CH, Castillo PE, Chandra SS | title = Synucleins regulate the kinetics of synaptic vesicle endocytosis | journal = The Journal of Neuroscience| volume = 34 | issue = 28 | pages = 9364–9376 | date = July 2014 | pmid = 25009269 | pmc = 4087213 | doi = 10.1523/JNEUROSCI.4787-13.2014 }}</ref><ref>{{cite journal | vauthors = Wang L, Das U, Scott DA, Tang Y, McLean PJ, Roy S | title = α-synuclein multimers cluster synaptic vesicles and attenuate recycling | journal = Current Biology | volume = 24 | issue = 19 | pages = 2319–2326 | date = October 2014 | pmid = 25264250 | pmc = 4190006 | doi = 10.1016/j.cub.2014.08.027 | bibcode = 2014CBio...24.2319W }}</ref><ref name="Sun_2019">{{cite journal | vauthors = Sun J, Wang L, Bao H, Premi S, Das U, Chapman ER, Roy S | title = Functional cooperation of α-synuclein and VAMP2 in synaptic vesicle recycling | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 116 | issue = 23 | pages = 11113–11115 | date = June 2019 | pmid = 31110017 | pmc = 6561242 | doi = 10.1073/pnas.1903049116 | bibcode = 2019PNAS..11611113S | doi-access = free }}</ref> An alternate view is that alpha-synuclein binds to [[VAMP2]] (a [[synaptobrevin]]) and stabilizes [[SNARE (protein)|SNARE complexes]];<ref name="Burre_2010" /><ref>{{cite journal | vauthors = Burré J, Sharma M, Südhof TC | title = Cell Biology and Pathophysiology of α-Synuclein | journal = Cold Spring Harbor Perspectives in Medicine | volume = 8 | issue = 3 | pages = a024091 | date = March 2018 | pmid = 28108534 | pmc = 5519445 | doi = 10.1101/cshperspect.a024091 }}</ref><ref>{{cite journal | vauthors = Burré J, Sharma M, Südhof TC | title = Systematic mutagenesis of α-synuclein reveals distinct sequence requirements for physiological and pathological activities | journal = The Journal of Neuroscience| volume = 32 | issue = 43 | pages = 15227–15242 | date = October 2012 | pmid = 23100443 | pmc = 3506191 | doi = 10.1523/JNEUROSCI.3545-12.2012 }}</ref><ref>{{cite journal | vauthors = Burré J, Sharma M, Südhof TC | title = α-Synuclein assembles into higher-order multimers upon membrane binding to promote SNARE complex formation | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 111 | issue = 40 | pages = E4274–E4283 | date = October 2014 | pmid = 25246573 | pmc = 4210039 | doi = 10.1073/pnas.1416598111 | doi-access = free | bibcode = 2014PNAS..111E4274B }}</ref><ref name="Diao_2013">{{cite journal | vauthors = Diao J, Burré J, Vivona S, Cipriano DJ, Sharma M, Kyoung M, Südhof TC, Brunger AT | title = Native α-synuclein induces clustering of synaptic-vesicle mimics via binding to phospholipids and synaptobrevin-2/VAMP2 | journal = eLife | volume = 2 | pages = e00592 | date = April 2013 | pmid = 23638301 | pmc = 3639508 | doi = 10.7554/eLife.00592 | doi-access = free }}</ref> though recent studies indicate that alpha-synuclein–VAMP2 binding is critical for alpha-synuclein-mediated attenuation of synaptic vesicle recycling, connecting the two seemingly divergent views.<ref name="Sun_2019" /> It may also help regulate the release of [[dopamine]], a type of neurotransmitter that is critical for controlling the start and stop of voluntary and involuntary movements.<ref name="ghrsnca" />

Alpha-synuclein modulates [[DNA repair]] processes, including repair of [[double-strand break]]s (DSBs).<ref name="Schaser_2019">{{cite journal | vauthors = Schaser AJ, Osterberg VR, Dent SE, Stackhouse TL, Wakeham CM, Boutros SW, Weston LJ, Owen N, Weissman TA, Luna E, Raber J, Luk KC, McCullough AK, Woltjer RL, Unni VK | title = Alpha-synuclein is a DNA binding protein that modulates DNA repair with implications for Lewy body disorders | journal = Scientific Reports | volume = 9 | issue = 1 | pages = 10919 | date = July 2019 | pmid = 31358782 | pmc = 6662836 | doi = 10.1038/s41598-019-47227-z | bibcode = 2019NatSR...910919S }}</ref> [[DNA damage (naturally occurring)|DNA damage]] response markers co-localize with alpha-synuclein to form discrete foci in human cells and mouse brain. Depletion of alpha-synuclein in human cells causes increased introduction of DNA DSBs after exposure to [[bleomycin]] and reduced ability to repair these DSBs. In addition, alpha-synuclein [[knockout mouse|knockout mice]] display a higher level of DSBs, and this problem can be alleviated by transgenic reintroduction of human alpha-synuclein. Alpha-synuclein promotes the DSB repair pathway referred to as [[non-homologous end joining]].<ref name="Schaser_2019" /> The DNA repair function of alpha-synuclein appears to be compromised in [[Lewy body]] inclusion bearing neurons, and this may trigger cell death.

===Proneurogenic function of alpha-synuclein===
In some [[neurodegenerative diseases]], alpha-synuclein produces insoluble [[inclusion bodies]]. These diseases, known as [[synucleinopathies]], are connected with either higher levels of normal alpha-synuclein or its mutant variants.<ref>{{cite journal | vauthors = Ryskalin L, Busceti CL, Limanaqi F, Biagioni F, Gambardella S, Fornai F | title = A Focus on the Beneficial Effects of Alpha Synuclein and a Re-Appraisal of Synucleinopathies | journal = Current Protein & Peptide Science | volume = 19 | issue = 6 | pages = 598–611 | year = 2018 | pmid = 29150919 | pmc = 5925871 | doi = 10.2174/1389203718666171117110028 }}</ref> The normal physiological role of Snca, however, has not yet been thoroughly explained. In fact, physiological Snca has been demonstrated to have a neuroprotective impact by inhibiting apoptosis induced by several types of apoptotic stimuli, or by regulating the expression of proteins involved in apoptotic pathways.
Recently it has been demonstrated that up-regulation of alpha-synuclein in the dentate gyrus  (a neurogenic niche where new neurons are generated throughout life) activates stem cells, in a model of premature neural aging. This model shows reduced expression of alpha-synuclein and reduced proliferation of stem cells, as is physiologically observed during aging. Exogenous alpha-synuclein in the dentate gyrus is able to rescue this defect. Moreover, alpha-synuclein also boosts the proliferation of dentate gyrus progenitor neural cells in wild-type young mice. Thus, alpha-synuclein represents an effector for neural stem and progenitor cell activation.<ref>{{cite journal | vauthors = Micheli L, Creanza TM, Ceccarelli M, D'Andrea G, Giacovazzo G, Ancona N, Coccurello R, Scardigli R, Tirone F | title = Transcriptome Analysis in a Mouse Model of Premature Aging of Dentate Gyrus: Rescue of Alpha-Synuclein Deficit by Virus-Driven Expression or by Running Restores the Defective Neurogenesis | journal = Frontiers in Cell and Developmental Biology | volume = 9 | pages = 696684 | year = 2021 | pmid = 34485283 | pmc = 8415876 | doi = 10.3389/fcell.2021.696684 | doi-access = free }}</ref>
Similarly, alpha-synuclein has been found to be required to maintain stem cells of the SVZ (subventricular zone, i.e., another neurogenic niche) in a cycling state.<ref>{{cite journal | vauthors = Perez-Villalba A, Sirerol-Piquer MS, Belenguer G, Soriano-Cantón R, Muñoz-Manchado AB, Villadiego J, Alarcón-Arís D, Soria FN, Dehay B, Bezard E, Vila M, Bortolozzi A, Toledo-Aral JJ, Pérez-Sánchez F, Fariñas I | title = Synaptic Regulator α-Synuclein in Dopaminergic Fibers Is Essentially Required for the Maintenance of Subependymal Neural Stem Cells | journal = The Journal of Neuroscience| volume = 38 | issue = 4 | pages = 814–825 | date = January 2018 | pmid = 29217686 | pmc = 6596232 | doi = 10.1523/JNEUROSCI.2276-17.2017 }}</ref>