Alpha-Synuclein Pathophysiology in Neurodegenerative Disorders: A Review Focusing on Molecular Mechanisms and Treatment Advances in Parkinson’s Disease

Abeliovich A, Schmitz Y, Fariñas I, Choi-Lundberg D, Ho W-H, Castillo PE, Shinsky N, Verdugo JMG, Armanini M, Ryan A (2000) Mice lacking α-synuclein display functional deficits in the nigrostriatal dopamine system. Neuron 25(1):239–252

Article  CAS  PubMed  Google Scholar 

Alarcón-Arís D, Recasens A, Galofré M, Carballo-Carbajal I, Zacchi N, Ruiz-Bronchal E, Pavia-Collado R, Chica R, Ferrés-Coy A, Santos M, Revilla R, Montefeltro A, Fariñas I, Artigas F, Vila M, Bortolozzi A (2018) Selective α-synuclein knockdown in monoamine neurons by intranasal oligonucleotide delivery: potential therapy for Parkinson’s Disease. Mol Ther 26(2):550–567. https://doi.org/10.1016/j.ymthe.2017.11.015

Article  CAS  PubMed  Google Scholar 

Phenylbutyrate Response As a Biomarker for Alpha-Synuclein Clearance From Brain (2014) https://clinicaltrials.gov/study/NCT02046434.

Attar A, Ripoli C, Riccardi E, Maiti P, Li Puma DD, Liu T, Hayes J, Jones MR, Lichti-Kaiser K, Yang F, Gale GD, Tseng CH, Tan M, Xie CW, Straudinger JL, Klärner FG, Schrader T, Frautschy SA, Grassi C, Bitan G (2012) Protection of primary neurons and mouse brain from Alzheimer’s pathology by molecular tweezers. Brain 135(Pt 12):3735–3748. https://doi.org/10.1093/brain/aws289

Article  PubMed  PubMed Central  Google Scholar 

Aulić S, Le TT, Moda F, Abounit S, Corvaglia S, Casalis L, Gustincich S, Zurzolo C, Tagliavini F, Legname G (2014) Defined α-synuclein prion-like molecular assemblies spreading in cell culture. BMC Neurosci 15:69. https://doi.org/10.1186/1471-2202-15-69

Article  CAS  PubMed  PubMed Central  Google Scholar 

Auluck PK, Bonini NM (2002) Pharmacological prevention of Parkinson disease in Drosophila. Nat Med 8(11):1185–1186. https://doi.org/10.1038/nm1102-1185

Article  CAS  PubMed  Google Scholar 

Auluck PK, Meulener MC, Bonini NM (2005) Mechanisms of suppression of α-synuclein neurotoxicity by geldanamycin in drosophila. J Biol Chem 280(4):2873–2878. https://doi.org/10.1074/jbc.M412106200

Article  CAS  PubMed  Google Scholar 

Baba Y, Kuroiwa A, Uitti RJ, Wszolek ZK, Yamada T (2005) Alterations of T-lymphocyte populations in Parkinson disease. Parkinsonism Relat Disord 11(8):493–498. https://doi.org/10.1016/j.parkreldis.2005.07.005

Article  PubMed  Google Scholar 

Batelli S, Albani D, Rametta R, Polito L, Prato F, Pesaresi M, Negro A, Forloni G (2008) DJ-1 modulates alpha-synuclein aggregation state in a cellular model of oxidative stress: relevance for Parkinson’s disease and involvement of HSP70. PLoS ONE 3(4):e1884. https://doi.org/10.1371/journal.pone.0001884

Article  CAS  PubMed  PubMed Central  Google Scholar 

Beach TG, Adler CH, Lue L, Sue LI, Bachalakuri J, Henry-Watson J, Sasse J, Boyer S, Shirohi S, Brooks R (2009) Unified staging system for Lewy body disorders: correlation with nigrostriatal degeneration, cognitive impairment and motor dysfunction. Acta Neuropathol 117:613–634

Article  PubMed  PubMed Central  Google Scholar 

Bendor JT, Logan TP, Edwards RH (2013) The function of α-synuclein. Neuron 79(6):1044–1066

Article  CAS  PubMed  Google Scholar 

Bengoa-Vergniory N, Faggiani E, Ramos-Gonzalez P, Kirkiz E, Connor-Robson N, Brown LV, Siddique I, Li Z, Vingill S, Cioroch M, Cavaliere F, Threlfell S, Roberts B, Schrader T, Klärner FG, Cragg S, Dehay B, Bitan G, Matute C, Bezard E, Wade-Martins R (2020) CLR01 protects dopaminergic neurons in vitro and in mouse models of Parkinson’s disease. Nat Commun 11(1):4885. https://doi.org/10.1038/s41467-020-18689-x

Article  CAS  PubMed  PubMed Central  Google Scholar 

Benskey MJ, Sellnow RC, Sandoval IM, Sortwell CE, Lipton JW, Manfredsson FP (2018) Silencing alpha synuclein in mature nigral neurons results in rapid neuroinflammation and subsequent toxicity. Front Mol Neurosci 11:36

Article  PubMed  PubMed Central  Google Scholar 

Berezovski MV (2024) Breaking bad aggregates: How a DNA aptamer cleans up Parkinson’s disease. Mol Ther Nucleic Acids. https://doi.org/10.1016/j.omtn.2024.102296

Article  PubMed  PubMed Central  Google Scholar 

Bergström AL, Kallunki P, Fog K (2016) Development of passive immunotherapies for Synucleinopathies. Mov Disord 31(2):203–213. https://doi.org/10.1002/mds.26481

Article  CAS  PubMed  Google Scholar 

Bieri G, Gitler AD, Brahic M (2018) Internalization, axonal transport and release of fibrillar forms of alpha-synuclein. Neurobiol Dis 109:219–225

Article  CAS  PubMed  Google Scholar 

Binger KJ, Ecroyd H, Yang S, Carver JA, Howlett GJ, Griffin MD (2013) Avoiding the oligomeric state: αB-crystallin inhibits fragmentation and induces dissociation of apolipoprotein C-II amyloid fibrils. Faseb J 27(3):1214–1222. https://doi.org/10.1096/fj.12-220657

Article  CAS  PubMed  Google Scholar 

Bloem BR, Okun MS, Klein C (2021) Parkinson’s disease. The Lancet 397(10291):2284–2303

Article  CAS  Google Scholar 

Book A, Guella I, Candido T, Brice A, Hattori N, Jeon B, Farrer MJ, Consortium SMIotG (2018) A meta-analysis of α-synuclein multiplication in familial parkinsonism. Front Neurol 9:1021

Article  Google Scholar 

Boyer DR, Li B, Sun C, Fan W, Sawaya MR, Jiang L, Eisenberg DS (2019) Structures of fibrils formed by α-synuclein hereditary disease mutant H50Q reveal new polymorphs. Nat Struct Mol Biol 26(11):1044–1052

Article  CAS  PubMed  PubMed Central  Google Scholar 

Braczynski AK, Schulz JB, Bach JP (2017) Vaccination strategies in tauopathies and synucleinopathies. J Neurochem 143(5):467–488. https://doi.org/10.1111/jnc.14207

Article  CAS  PubMed  Google Scholar 

Brandis KA, Holmes IF, England SJ, Sharma N, Kukreja L, DebBurman SK (2006) α-synuclein fission yeast model: Concentration—Department aggregation without plasma membrane localization or toxicity. J Mol Neurosci 28:179–191

Article  CAS  PubMed  Google Scholar 

Brenner S, Wersinger C, Gasser T (2015) Transcriptional regulation of the α-synuclein gene in human brain tissue. Neurosci Lett 599:140–145

Article  CAS  PubMed  Google Scholar 

Brochard V, Combadière B, Prigent A, Laouar Y, Perrin A, Beray-Berthat V, Bonduelle O, Alvarez-Fischer D, Callebert J, Launay JM, Duyckaerts C, Flavell RA, Hirsch EC, Hunot S (2009) Infiltration of CD4+ lymphocytes into the brain contributes to neurodegeneration in a mouse model of Parkinson disease. J Clin Invest 119(1):182–192. https://doi.org/10.1172/jci36470

Article  CAS  PubMed  Google Scholar 

Bruinsma IB, Bruggink KA, Kinast K, Versleijen AA, Segers-Nolten IM, Subramaniam V, Kuiperij HB, Boelens W, de Waal RM, Verbeek MM (2011) Inhibition of α-synuclein aggregation by small heat shock proteins. Proteins 79(10):2956–2967. https://doi.org/10.1002/prot.23152

Article  CAS  PubMed  Google Scholar 

Brys M, Fanning L, Hung S, Ellenbogen A, Penner N, Yang M, Welch M, Koenig E, David E, Fox T, Makh S, Aldred J, Goodman I, Pepinsky B, Liu Y, Graham D, Weihofen A, Cedarbaum JM (2019) Randomized phase I clinical trial of anti-α-synuclein antibody BIIB054. Mov Disord 34(8):1154–1163. https://doi.org/10.1002/mds.27738

Article  CAS  PubMed  PubMed Central  Google Scholar 

Burré J, Sharma M, Tsetsenis T, Buchman V, Etherton MR, Südhof TC (2010) α-Synuclein promotes SNARE-complex assembly in vivo and in vitro. Science 329(5999):1663–1667

Article  PubMed  PubMed Central  Google Scholar 

Burré J, Sharma M, Südhof TC (2014) α-Synuclein assembles into higher-order multimers upon membrane binding to promote SNARE complex formation. Proc Natl Acad Sci 111(40):E4274–E4283

Article  PubMed  PubMed Central  Google Scholar 

Burré J, Sharma M, Südhof TC (2015) Definition of a molecular pathway mediating α-synuclein neurotoxicity. J Neurosci 35(13):5221–5232

Article  PubMed 

Comments (0)

No login
gif