Poewe, W. et al. Parkinson disease. Nat. Rev. Dis. Prim. 3, 17013 (2017).

Article  PubMed  Google Scholar 

Braak, H. et al. Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol. Aging 24, 197–211 (2003).

Article  PubMed  Google Scholar 

Jankovic, J. Parkinson’s disease: clinical features and diagnosis. J. Neurol. Neurosurg. Psychiatry 79, 368–376 (2008).

Article  CAS  PubMed  Google Scholar 

Blauwendraat, C., Nalls, M. A. & Singleton, A. B. The genetic architecture of Parkinson’s disease. Lancet Neurol. 19, 170–178 (2020).

Article  CAS  PubMed  Google Scholar 

Jia, F., Fellner, A. & Kumar, K. R. Monogenic Parkinson’s disease: genotype, phenotype, pathophysiology, and genetic testing. Genes 13, 471 (2022).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Nalls, M. A. et al. Identification of novel risk loci, causal insights, and heritable risk for Parkinson’s disease: a meta-analysis of genome-wide association studies. Lancet Neurol. 18, 1091–1102 (2019).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Kim, J. J. et al. Multi-ancestry genome-wide association meta-analysis of Parkinson’s disease. Nat. Genet. 56, 27–36 (2024).

Article  CAS  PubMed  Google Scholar 

Rizig, M. et al. Identification of genetic risk loci and causal insights associated with Parkinson’s disease in African and African admixed populations: a genome-wide association study. Lancet Neurol. 22, 1015–1025 (2023).

Article  CAS  PubMed  Google Scholar 

Ball, N., Teo, W. P., Chandra, S. & Chapman, J. Parkinson’s disease and the environment. Front. Neurol. 10, 218 (2019).

Article  PubMed  PubMed Central  Google Scholar 

Tansey, M. G. et al. Inflammation and immune dysfunction in Parkinson disease. Nat. Rev. Immunol. 22, 657–673 (2022).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Kam, T. I., Hinkle, J. T., Dawson, T. M. & Dawson, V. L. Microglia and astrocyte dysfunction in Parkinson’s disease. Neurobiol. Dis. 144, 105028 (2020).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Bjorklund, G., Hofer, T., Nurchi, V. M. & Aaseth, J. Iron and other metals in the pathogenesis of Parkinson’s disease: toxic effects and possible detoxification. J. Inorg. Biochem. 199, 110717 (2019).

Article  PubMed  Google Scholar 

Polymeropoulos, M. H. et al. Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science 276, 2045–2047 (1997).

Article  CAS  PubMed  Google Scholar 

Singleton, A. B. et al. alpha-Synuclein locus triplication causes Parkinson’s disease. Science 302, 841 (2003).

Article  CAS  PubMed  Google Scholar 

Giasson, B. I., Murray, I. V., Trojanowski, J. Q. & Lee, V. M. A hydrophobic stretch of 12 amino acid residues in the middle of alpha-synuclein is essential for filament assembly. J. Biol. Chem. 276, 2380–2386 (2001).

Article  CAS  PubMed  Google Scholar 

Luk, K. C. et al. Pathological alpha-synuclein transmission initiates Parkinson-like neurodegeneration in nontransgenic mice. Science 338, 949–953 (2012).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Conway, K. A., Harper, J. D. & Lansbury, P. T. Accelerated in vitro fibril formation by a mutant alpha-synuclein linked to early-onset Parkinson disease. Nat. Med. 4, 1318–1320 (1998).

Article  CAS  PubMed  Google Scholar 

Masliah, E. et al. Dopaminergic loss and inclusion body formation in alpha-synuclein mice: implications for neurodegenerative disorders. Science 287, 1265–1269 (2000). This work is, to our knowledge, the first to model overexpression of human α-synuclein in mice, which developed Lewy body-like inclusions, dopaminergic neuron terminal loss and motor deficits.

Article  CAS  PubMed  Google Scholar 

Outeiro, T. F. & Lindquist, S. Yeast cells provide insight into alpha-synuclein biology and pathobiology. Science 302, 1772–1775 (2003).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Burre, J. et al. Alpha-synuclein promotes SNARE-complex assembly in vivo and in vitro. Science 329, 1663–1667 (2010). This paper provides evidence for a physiological role of α-synuclein in SNARE complex assembly through association with VAMP2.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Nemani, V. M. et al. Increased expression of alpha-synuclein reduces neurotransmitter release by inhibiting synaptic vesicle reclustering after endocytosis. Neuron 65, 66–79 (2010).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Runwal, G. M. & Edwards, R. H. The role of alpha-synuclein in exocytosis. Exp. Neurol. 373, 114668 (2024).

Article  CAS  PubMed  Google Scholar 

Wong, Y. C. & Krainc, D. α-Synuclein toxicity in neurodegeneration: mechanism and therapeutic strategies. Nat. Med. 23, 1–13 (2017).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Vogiatzi, T., Xilouri, M., Vekrellis, K. & Stefanis, L. Wild type alpha-synuclein is degraded by chaperone-mediated autophagy and macroautophagy in neuronal cells. J. Biol. Chem. 283, 23542–23556 (2008).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Robak, L. A. et al. Excessive burden of lysosomal storage disorder gene variants in Parkinson’s disease. Brain 140, 3191–3203 (2017).

Article  PubMed  PubMed Central  Google Scholar 

Sevlever, D., Jiang, P. & Yen, S. H. Cathepsin D is the main lysosomal enzyme involved in the degradation of alpha-synuclein and generation of its carboxy-terminally truncated species. Biochemistry 47, 9678–9687 (2008).

Article  CAS  PubMed  Google Scholar 

Qiao, L. et al. Lysosomal enzyme cathepsin D protects against alpha-synuclein aggregation and toxicity. Mol. Brain 1, 17 (2008).

Article  PubMed  PubMed Central  Google Scholar 

Chang, D. et al. A meta-analysis of genome-wide association studies identifies 17 new Parkinson’s disease risk loci. Nat. Genet. 49, 1511–1516 (2017).

Article  CAS  PubMed  PubMed Central  Google Scholar 

McGlinchey, R. P. & Lee, J. C. Cysteine cathepsins are essential in lysosomal degradation of alpha-synuclein. Proc. Natl Acad. Sci. USA 112, 9322–9327 (2015).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Cuervo, A. M., Stefanis, L., Fredenburg, R., Lansbury, P. T. & Sulzer, D. Impaired degradation of mutant alpha-synuclein by chaperone-mediated autophagy. Science 305, 1292–1295 (2004).

Article  CAS  PubMed  Google Scholar 

Manzanza, N. O., Sedlackova, L. & Kalaria, R. N. Alpha-synuclein post-translational modifications: implications for pathogenesis of Lewy body disorders. Front. Aging Neurosci. 13, 690293 (2021).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Giasson, B. I. et al. Oxidative damage linked to neurodegeneration by selective alpha-synuclein nitration in synucleinopathy lesions. Science 290, 985–989 (2000).

Article  CAS  PubMed  Google Scholar 

Souza, J. M., Giasson, B. I., Chen, Q., Lee, V. M. & Ischiropoulos, H. Dityrosine cross-linking promotes formation of stable alpha-synuclein polymers. Implication of nitrative and oxidative stress in the pathogenesis of neurodegenerative synucleinopathies. J. Biol. Chem. 275, 18344–18349 (2000).

Article  CAS  PubMed  Google Scholar 

Fujiwara, H. et al. alpha-Synuclein is phosphorylated in synucleinopathy lesions. Nat. Cell Biol. 4, 160–164 (2002).

Article  CAS  PubMed  Google Scholar 

Mahul-Mellier, A. L. et al. c-Abl phosphorylates alpha-synuclein and regulates its degradation: implication for alpha-synuclein clearance and contribution to the pathogenesis of Parkinson’s disease. Hum. Mol. Genet. 23, 2858–2879 (2014).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Burmann, B. M. et al. Regulation of alpha-synuclein by chaperones in mammalian cells. Nature 577, 127–132 (2020).

Article  CAS  PubMed