REFERENCES
2. Hou Y, Dan X, Babbar M, et al. Ageing as a risk factor for neurodegenerative disease. Nat Rev Neurol 2019;15:565-81.
4. Bendig J, Frank A, Reichmann H. Aging and Parkinson’s disease: a complex interplay of vulnerable neurons, the immune system and the blood-brain barrier. Ageing Neur Dis 2024;4:5.
5. Estaun-Panzano J, Arotcarena ML, Bezard E. Monitoring α-synuclein aggregation. Neurobiol Dis 2023;176:105966.
6. McCormack A, Chegeni N, Chegini F, et al. Purification of α-synuclein containing inclusions from human post mortem brain tissue. J Neurosci Methods 2016;266:141-50.
7. Maroteaux L, Campanelli JT, Scheller RH. Synuclein: a neuron-specific protein localized to the nucleus and presynaptic nerve terminal. J Neurosci 1988;8:2804-15.
8. Schaser AJ, Osterberg VR, Dent SE, et al. Alpha-synuclein is a DNA binding protein that modulates DNA repair with implications for Lewy body disorders. Sci Rep 2019;9:10919.
9. Li J, Henning Jensen P, Dahlström A. Differential localization of alpha-, beta- and gamma-synucleins in the rat CNS. Neuroscience 2002;113:463-78.
10. Burré J, Sharma M, Südhof TC. Cell biology and pathophysiology of α-synuclein. Cold Spring Harb Perspect Med 2018;8:a024091.
11. Burré J, Sharma M, Tsetsenis T, Buchman V, Etherton MR, Südhof TC. Alpha-synuclein promotes SNARE-complex assembly in vivo and in vitro. Science 2010;329:1663-7.
12. Böttner M, Fricke T, Müller M, et al. Alpha-synuclein is associated with the synaptic vesicle apparatus in the human and rat enteric nervous system. Brain Res 2015;1614:51-9.
13. Scott DA, Tabarean I, Tang Y, Cartier A, Masliah E, Roy S. A pathologic cascade leading to synaptic dysfunction in alpha-synuclein-induced neurodegeneration. J Neurosci 2010;30:8083-95.
14. Faustini G, Marchesan E, Zonta L, et al. Alpha-synuclein preserves mitochondrial fusion and function in neuronal cells. Oxid Med Cell Longev 2019;2019:4246350.
15. Guiney SJ, Adlard PA, Lei P, et al. Fibrillar α-synuclein toxicity depends on functional lysosomes. J Biol Chem 2020;295:17497-513.
16. Domert J, Sackmann C, Severinsson E, et al. Aggregated alpha-synuclein transfer efficiently between cultured human neuron-like cells and localize to lysosomes. PLoS One 2016;11:e0168700.
17. Seebauer L, Schneider Y, Drobny A, et al. Interaction of alpha synuclein and microtubule organization is linked to impaired neuritic integrity in Parkinson’s patient-derived neuronal cells. Int J Mol Sci 2022;23:1812.
18. Mazzetti S, Calogero AM, Pezzoli G, Cappelletti G. Cross-talk between α-synuclein and the microtubule cytoskeleton in neurodegeneration. Exp Neurol 2023;359:114251.
19. Wang ZL, Yuan L, Li W, Li JY. Ferroptosis in Parkinson’s disease: glia-neuron crosstalk. Trends Mol Med 2022;28:258-69.
20. Mavroeidi P, Xilouri M. Neurons and glia interplay in α-synucleinopathies. Int J Mol Sci 2021;22:4994.
21. Masliah E, Rockenstein E, Veinbergs I, et al. Dopaminergic loss and inclusion body formation in alpha-synuclein mice: implications for neurodegenerative disorders. Science 2000;287:1265-9.
22. Janezic S, Threlfell S, Dodson PD, et al. Deficits in dopaminergic transmission precede neuron loss and dysfunction in a new Parkinson model. Proc Natl Acad Sci U S A 2013;110:E4016-25.
23. Winner B, Jappelli R, Maji SK, et al. In vivo demonstration that alpha-synuclein oligomers are toxic. Proc Natl Acad Sci U S A 2011;108:4194-9.
24. Galvin JE, Schuck TM, Lee VM, Trojanowski JQ. Differential expression and distribution of alpha-, beta-, and gamma-synuclein in the developing human substantia nigra. Exp Neurol 2001;168:347-55.
25. Raghavan R, Kruijff Ld, Sterrenburg MD, Rogers BB, Hladik CL, White CL 3rd. Alpha-synuclein expression in the developing human brain. Pediatr Dev Pathol 2004;7:506-16.
26. Saha AR, Hill J, Utton MA, et al. Parkinson’s disease alpha-synuclein mutations exhibit defective axonal transport in cultured neurons. J Cell Sci 2004;117:1017-24.
27. Petersen K, Olesen OF, Mikkelsen JD. Developmental expression of alpha-synuclein in rat hippocampus and cerebral cortex. Neuroscience 1999;91:651-9.
28. Chu Y, Kordower JH. Age-associated increases of alpha-synuclein in monkeys and humans are associated with nigrostriatal dopamine depletion: is this the target for Parkinson’s disease?. Neurobiol Dis 2007;25:134-49.
29. Li X, Yang W, Li X, Chen M, Liu C, Yu S. Age-dependent elevations of oligomeric and phosphorylated alpha-synuclein synchronously occurs in the brain and gastrointestinal tract of cynomolgus monkeys. Neurosci Lett 2018;662:276-82.
30. Canron MH, Perret M, Vital A, Bézard E, Dehay B. Age-dependent α-synuclein aggregation in the Microcebus murinus lemur primate. Sci Rep 2012;2:910.
31. Perez RG, Waymire JC, Lin E, Liu JJ, Guo F, Zigmond MJ. A role for alpha-synuclein in the regulation of dopamine biosynthesis. J Neurosci 2002;22:3090-9.
32. Peng X, Tehranian R, Dietrich P, Stefanis L, Perez RG. Alpha-synuclein activation of protein phosphatase 2A reduces tyrosine hydroxylase phosphorylation in dopaminergic cells. J Cell Sci 2005;118:3523-30.
33. Tehranian R, Montoya SE, Van Laar AD, Hastings TG, Perez RG. Alpha-synuclein inhibits aromatic amino acid decarboxylase activity in dopaminergic cells. J Neurochem 2006;99:1188-96.
34. Lotharius J, Brundin P. Pathogenesis of Parkinson’s disease: dopamine, vesicles and alpha-synuclein. Nat Rev Neurosci 2002;3:932-42.
35. Vaughan RA, Foster JD. Mechanisms of dopamine transporter regulation in normal and disease states. Trends Pharmacol Sci 2013;34:489-96.
36. Lee FJ, Liu F, Pristupa ZB, Niznik HB. Direct binding and functional coupling of alpha-synuclein to the dopamine transporters accelerate dopamine-induced apoptosis. FASEB J 2001;15:916-26.
37. Guo JT, Chen AQ, Kong Q, Zhu H, Ma CM, Qin C. Inhibition of vesicular monoamine transporter-2 activity in alpha-synuclein stably transfected SH-SY5Y cells. Cell Mol Neurobiol 2008;28:35-47.
38. Meredith GE, Totterdell S, Petroske E, Santa Cruz K, Callison RC Jr, Lau YS. Lysosomal malfunction accompanies alpha-synuclein aggregation in a progressive mouse model of Parkinson’s disease. Brain Res 2002;956:156-65.
39. Li W, Englund E, Widner H, et al. Extensive graft-derived dopaminergic innervation is maintained 24 years after transplantation in the degenerating parkinsonian brain. Proc Natl Acad Sci U S A 2016;113:6544-9.
40. Li JY, Englund E, Holton JL, et al. Lewy bodies in grafted neurons in subjects with Parkinson’s disease suggest host-to-graft disease propagation. Nat Med 2008;14:501-3.
41. Tao-Cheng JH. Immunogold labeling of synaptic vesicle proteins in developing hippocampal neurons. Mol Brain 2020;13:9.
42. Pieger K, Schmitt V, Gauer C, et al. Translocation of distinct alpha synuclein species from the nucleus to neuronal processes during neuronal differentiation. Biomolecules 2022;12:1108.
43. Chen K, Guo Y, Lei P, Finkelstein DI. Can alpha-synuclein be both the cause and a consequence of Parkinson’s disease?. Ageing Neur Dis 2023;3:10.
44. Tanji K, Mori F, Mimura J, et al. Proteinase K-resistant alpha-synuclein is deposited in presynapses in human Lewy body disease and A53T alpha-synuclein transgenic mice. Acta Neuropathol 2010;120:145-54.
45. Neumann M, Müller V, Kretzschmar HA, Haass C, Kahle PJ. Regional distribution of proteinase K-resistant alpha-synuclein correlates with Lewy body disease stage. J Neuropathol Exp Neurol 2004;63:1225-35.
46. Björklund A, Dunnett SB, Brundin P, et al. Neural transplantation for the treatment of Parkinson’s disease. Lancet Neurol 2003;2:437-45.
47. Li JY, Li W. Postmortem studies of fetal grafts in Parkinson’s disease: what lessons have we learned?. Front Cell Dev Biol 2021;9:666675.
48. Hagell P, Schrag A, Piccini P, et al. Sequential bilateral transplantation in Parkinson’s disease: effects of the second graft. Brain 1999;122:1121-32.
49. Kordower JH, Chu Y, Hauser RA, Freeman TB, Olanow CW. Lewy body-like pathology in long-term embryonic nigral transplants in Parkinson’s disease. Nat Med 2008;14:504-6.
50. Kordower JH, Chu Y, Hauser RA, Olanow CW, Freeman TB. Transplanted dopaminergic neurons develop PD pathologic changes: a second case report. Mov Disord 2008;23:2303-6.
52. Li JY, Englund E, Widner H, et al. Characterization of Lewy body pathology in 12- and 16-year-old intrastriatal mesencephalic grafts surviving in a patient with Parkinson’s disease. Mov Disord 2010;25:1091-6.
53. Kurowska Z, Englund E, Widner H, Lindvall O, Li JY, Brundin P. Signs of degeneration in 12-22-year old grafts of mesencephalic dopamine neurons in patients with Parkinson’s disease. J Parkinsons Dis 2011;1:83-92.
54. Van Den Berge N, Ferreira N, Mikkelsen TW, et al. Ageing promotes pathological alpha-synuclein propagation and autonomic dysfunction in wild-type rats. Brain 2021;144:1853-68.
55. Barker RA; TRANSEURO consortium. Designing stem-cell-based dopamine cell replacement trials for Parkinson’s disease. Nat Med 2019;25:1045-53.
56. Olanow CW, Savolainen M, Chu Y, Halliday GM, Kordower JH. Temporal evolution of microglia and α-synuclein accumulation following foetal grafting in Parkinson’s disease. Brain 2019;142:1690-700.
57. Piccini P, Brooks DJ, Björklund A, et al. Dopamine release from nigral transplants visualized in vivo in a Parkinson’s patient. Nat Neurosci 1999;2:1137-40.
58. Angot E, Steiner JA, Hansen C, Li JY, Brundin P. Are synucleinopathies prion-like disorders?. Lancet Neurol 2010;9:1128-38.
59. Hansen C, Li JY. Beyond α-synuclein transfer: pathology propagation in Parkinson’s disease. Trends Mol Med 2012;18:248-55.
60. Lázaro DF, Lee VM. Navigating through the complexities of synucleinopathies: Insights into pathogenesis, heterogeneity, and future perspectives. Neuron 2024;112:3029-42.
61. Peng C, Trojanowski JQ, Lee VM. Protein transmission in neurodegenerative disease. Nat Rev Neurol 2020;16:199-212.
62. Jucker M, Walker LC. Self-propagation of pathogenic protein aggregates in neurodegenerative diseases. Nature 2013;501:45-51.
63. Goedert M. NEURODEGENERATION. Alzheimer’s and Parkinson’s diseases: the prion concept in relation to assembled Aβ, tau, and α-synuclein. Science 2015;349:1255555.
64. Roos TT, Garcia MG, Martinsson I, et al. Neuronal spreading and plaque induction of intracellular Aβ and its disruption of Aβ homeostasis. Acta Neuropathol 2021;142:669-87.
65. Golomidov IM, Latypova EM, Ryabova EV, Bolshakova OI, Komissarov AE, Sarantseva SV. Reduction of the α-synuclein expression promotes slowing down early neuropathology development in the Drosophila model of Parkinson’s disease. J Neurogenet 2022;36:1-10.
66. Crabtree DM, Zhang J. Genetically engineered mouse models of Parkinson’s disease. Brain Res Bull 2012;88:13-32.
67. Niu Y, Guo X, Chen Y, et al. Early Parkinson’s disease symptoms in α-synuclein transgenic monkeys. Hum Mol Genet 2015;24:2308-17.
68. Li B, He D, Li X, Guo X. Modeling neurodegenerative diseases using non-human primates: advances and challenges. Ageing Neur Dis 2022;2:12.
69. Taylor TN, Potgieter D, Anwar S, et al. Region-specific deficits in dopamine, but not norepinephrine, signaling in a novel A30P α-synuclein BAC transgenic mouse. Neurobiol Dis 2014;62:193-207.
70. Visanji NP, Brotchie JM, Kalia LV, et al. α-Synuclein-based animal models of Parkinson’s disease: challenges and opportunities in a new era. Trends Neurosci 2016;39:750-62.
71. Decressac M, Mattsson B, Lundblad M, Weikop P, Björklund A. Progressive neurodegenerative and behavioural changes induced by AAV-mediated overexpression of α-synuclein in midbrain dopamine neurons. Neurobiol Dis 2012;45:939-53.
72. Kirik D, Annett LE, Burger C, Muzyczka N, Mandel RJ, Björklund A. Nigrostriatal alpha-synucleinopathy induced by viral vector-mediated overexpression of human alpha-synuclein: a new primate model of Parkinson’s disease. Proc Natl Acad Sci U S A 2003;100:2884-9.
73. Gonzalez-Rodriguez P, Zampese E, Surmeier DJ. Selective neuronal vulnerability in Parkinson’s disease. Prog Brain Res 2020;252:61-89.
74. Horsager J, Andersen KB, Knudsen K, et al. Brain-first versus body-first Parkinson’s disease: a multimodal imaging case-control study. Brain 2020;143:3077-88.
75. Dehay B, Vila M, Bezard E, Brundin P, Kordower JH. Alpha-synuclein propagation: new insights from animal models. Mov Disord 2016;31:161-8.
76. Double KL, Halliday GM. New face of neuromelanin. In: Riederer P, Reichmann H, Youdim MBH, Gerlach M, editors. Parkinson’s disease and related disorders. Vienna: Springer; 2006. pp. 119-23
77. Lee MK, Stirling W, Xu Y, et al. Human alpha-synuclein-harboring familial Parkinson’s disease-linked Ala-53 → Thr mutation causes neurodegenerative disease with alpha-synuclein aggregation in transgenic mice. Proc Natl Acad Sci U S A 2002;99:8968-73.
78. Kahle PJ, Neumann M, Ozmen L, et al. Selective insolubility of alpha-synuclein in human Lewy body diseases is recapitulated in a transgenic mouse model. Am J Pathol 2001;159:2215-25.
79. Fleming SM, Salcedo J, Fernagut PO, et al. Early and progressive sensorimotor anomalies in mice overexpressing wild-type human alpha-synuclein. J Neurosci 2004;24:9434-40.
80. Richfield EK, Thiruchelvam MJ, Cory-Slechta DA, et al. Behavioral and neurochemical effects of wild-type and mutated human alpha-synuclein in transgenic mice. Exp Neurol 2002;175:35-48.
81. Fujiwara H, Hasegawa M, Dohmae N, et al. alpha-Synuclein is phosphorylated in synucleinopathy lesions. Nat Cell Biol 2002;4:160-4.
82. van der Putten H, Wiederhold KH, Probst A, et al. Neuropathology in mice expressing human alpha-synuclein. J Neurosci 2000;20:6021-9.
83. Paleologou KE, Oueslati A, Shakked G, et al. Phosphorylation at S87 is enhanced in synucleinopathies, inhibits alpha-synuclein oligomerization, and influences synuclein-membrane interactions. J Neurosci 2010;30:3184-98.
84. Wakamatsu M, Ishii A, Ukai Y, et al. Accumulation of phosphorylated alpha-synuclein in dopaminergic neurons of transgenic mice that express human alpha-synuclein. J Neurosci Res 2007;85:1819-25.
85. Nuber S, Petrasch-Parwez E, Winner B, et al. Neurodegeneration and motor dysfunction in a conditional model of Parkinson’s disease. J Neurosci 2008;28:2471-84.
86. Neumann M, Kahle PJ, Giasson BI, et al. Misfolded proteinase K-resistant hyperphosphorylated alpha-synuclein in aged transgenic mice with locomotor deterioration and in human alpha-synucleinopathies. J Clin Invest 2002;110:1429-39.
87. Gallardo G, Schlüter OM, Südhof TC. A molecular pathway of neurodegeneration linking alpha-synuclein to ApoE and Abeta peptides. Nat Neurosci 2008;11:301-8.
88. Freichel C, Neumann M, Ballard T, et al. Age-dependent cognitive decline and amygdala pathology in alpha-synuclein transgenic mice. Neurobiol Aging 2007;28:1421-35.
89. Matsuoka Y, Vila M, Lincoln S, et al. Lack of nigral pathology in transgenic mice expressing human alpha-synuclein driven by the tyrosine hydroxylase promoter. Neurobiol Dis 2001;8:535-9.
90. Thiruchelvam MJ, Powers JM, Cory-Slechta DA, Richfield EK. Risk factors for dopaminergic neuron loss in human alpha-synuclein transgenic mice. Eur J Neurosci 2004;19:845-54.
91. Wakamatsu M, Ishii A, Iwata S, et al. Selective loss of nigral dopamine neurons induced by overexpression of truncated human alpha-synuclein in mice. Neurobiol Aging 2008;29:574-85.
92. Tofaris GK, Garcia Reitböck P, Humby T, et al. Pathological changes in dopaminergic nerve cells of the substantia nigra and olfactory bulb in mice transgenic for truncated human alpha-synuclein(1-120): implications for Lewy body disorders. J Neurosci 2006;26:3942-50.
93. Calabresi P, Di Lazzaro G, Marino G, Campanelli F, Ghiglieri V. Advances in understanding the function of alpha-synuclein: implications for Parkinson’s disease. Brain 2023;146:3587-97.
94. Cenci MA, Björklund A. Animal models for preclinical Parkinson’s research: an update and critical appraisal. Prog Brain Res 2020;252:27-59.
95. Tian Y, He M, Pan L, et al. Transgenic mice expressing human α-synuclein 1-103 fragment as a novel model of Parkinson’s disease. Front Aging Neurosci 2021;13:760781.
96. Giasson BI, Duda JE, Quinn SM, Zhang B, Trojanowski JQ, Lee VM. Neuronal alpha-synucleinopathy with severe movement disorder in mice expressing A53T human alpha-synuclein. Neuron 2002;34:521-33.
97. Oaks AW, Frankfurt M, Finkelstein DI, Sidhu A. Age-dependent effects of A53T alpha-synuclein on behavior and dopaminergic function. PLoS One 2013;8:e60378.
98. Hansen C, Björklund T, Petit GH, et al. A novel α-synuclein-GFP mouse model displays progressive motor impairment, olfactory dysfunction and accumulation of α-synuclein-GFP. Neurobiol Dis 2013;56:145-55.
99. Elabi O, Gaceb A, Carlsson R, et al. Human α-synuclein overexpression in a mouse model of Parkinson’s disease leads to vascular pathology, blood brain barrier leakage and pericyte activation. Sci Rep 2021;11:1120.
100. Zhong CB, Chen QQ, Haikal C, et al. Age-dependent alpha-synuclein accumulation and phosphorylation in the enteric nervous system in a transgenic mouse model of Parkinson’s disease. Neurosci Bull 2017;33:483-92.
101. Chen QQ, Haikal C, Li W, Li MT, Wang ZY, Li JY. Age-dependent alpha-synuclein accumulation and aggregation in the colon of a transgenic mouse model of Parkinson’s disease. Transl Neurodegener 2018;7:13.
102. Oliveira LM, Falomir-Lockhart LJ, Botelho MG, et al. Elevated α-synuclein caused by SNCA gene triplication impairs neuronal differentiation and maturation in Parkinson’s patient-derived induced pluripotent stem cells. Cell Death Dis 2015;6:e1994.
103. Singleton AB, Farrer M, Johnson J, et al. alpha-Synuclein locus triplication causes Parkinson’s disease. Science 2003;302:841.
104. Fuchs J, Nilsson C, Kachergus J, et al. Phenotypic variation in a large Swedish pedigree due to SNCA duplication and triplication. Neurology 2007;68:916-22
105. Chen L, Xie Z, Turkson S, Zhuang X. A53T human α-synuclein overexpression in transgenic mice induces pervasive mitochondria macroautophagy defects preceding dopamine neuron degeneration. J Neurosci 2015;35:890-905.
106. Masato A, Plotegher N, Terrin F, et al. DOPAL initiates αSynuclein-dependent impaired proteostasis and degeneration of neuronal projections in Parkinson’s disease. NPJ Parkinsons Dis 2023;9:42.
107. Kulkarni A, Preeti K, Tryphena KP, Srivastava S, Singh SB, Khatri DK. Proteostasis in Parkinson’s disease: recent development and possible implication in diagnosis and therapeutics. Ageing Res Rev 2023;84:101816.
108. Karabiyik C, Frake RA, Park SJ, Pavel M, Rubinsztein DC. Autophagy in ageing and ageing-related neurodegenerative diseases. AND 2021;1:2.
109. Shahpasandzadeh H, Popova B, Kleinknecht A, Fraser PE, Outeiro TF, Braus GH. Interplay between sumoylation and phosphorylation for protection against α-synuclein inclusions. J Biol Chem 2014;289:31224-40.
110. Lewis J, Melrose H, Bumcrot D, et al. In vivo silencing of alpha-synuclein using naked siRNA. Mol Neurodegener 2008;3:19.
111. Cooper JM, Wiklander PB, Nordin JZ, et al. Systemic exosomal siRNA delivery reduced alpha-synuclein aggregates in brains of transgenic mice. Mov Disord 2014;29:1476-85.
112. Rothaug M, Zunke F, Mazzulli JR, et al. LIMP-2 expression is critical for β-glucocerebrosidase activity and α-synuclein clearance. Proc Natl Acad Sci U S A 2014;111:15573-8.
113. Decressac M, Mattsson B, Weikop P, Lundblad M, Jakobsson J, Björklund A. TFEB-mediated autophagy rescues midbrain dopamine neurons from α-synuclein toxicity. Proc Natl Acad Sci U S A 2013;110:E1817-26.
114. Lindström V, Fagerqvist T, Nordström E, et al. Immunotherapy targeting α-synuclein protofibrils reduced pathology in (Thy-1)-h[A30P] α-synuclein mice. Neurobiol Dis 2014;69:134-43.
115. Schneeberger A, Tierney L, Mandler M. Active immunization therapies for Parkinson’s disease and multiple system atrophy. Mov Disord 2016;31:214-24.
116. Games D, Valera E, Spencer B, et al. Reducing C-terminal-truncated alpha-synuclein by immunotherapy attenuates neurodegeneration and propagation in Parkinson’s disease-like models. J Neurosci 2014;34:9441-54.
117. Tran HT, Chung CH, Iba M, et al. Α-synuclein immunotherapy blocks uptake and templated propagation of misfolded α-synuclein and neurodegeneration. Cell Rep 2014;7:2054-65.
118. Bergström AL, Kallunki P, Fog K. Development of passive immunotherapies for synucleinopathies. Mov Disord 2016;31:203-13.
119. Braak H, Del Tredici K, Rüb U, de Vos RA, Jansen Steur EN, Braak E. Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging 2003;24:197-211.
120. Desplats P, Lee HJ, Bae EJ, et al. Inclusion formation and neuronal cell death through neuron-to-neuron transmission of alpha-synuclein. Proc Natl Acad Sci U S A 2009;106:13010-5.
121. Hansen C, Angot E, Bergström AL, et al. α-Synuclein propagates from mouse brain to grafted dopaminergic neurons and seeds aggregation in cultured human cells. J Clin Invest 2011;121:715-25.
122. Luk KC, Kehm V, Carroll J, et al. Pathological α-synuclein transmission initiates Parkinson-like neurodegeneration in nontransgenic mice. Science 2012;338:949-53.
123. Luk KC, Kehm VM, Zhang B, O’Brien P, Trojanowski JQ, Lee VM. Intracerebral inoculation of pathological α-synuclein initiates a rapidly progressive neurodegenerative α-synucleinopathy in mice. J Exp Med 2012;209:975-86.
124. Surmeier DJ, Obeso JA, Halliday GM. Parkinson’s disease is not simply a prion disorder. J Neurosci 2017;37:9799-807.
125. Vargas JY, Grudina C, Zurzolo C. The prion-like spreading of α-synuclein: from in vitro to in vivo models of Parkinson’s disease. Ageing Res Rev 2019;50:89-101.
126. Peelaerts W, Bousset L, Baekelandt V, Melki R. ɑ-Synuclein strains and seeding in Parkinson’s disease, incidental Lewy body disease, dementia with Lewy bodies and multiple system atrophy: similarities and differences. Cell Tissue Res 2018;373:195-212.
127. Yuan L, Li JY. Exosomes in Parkinson’s disease: current perspectives and future challenges. ACS Chem Neurosci 2019;10:964-72.
128. Tam S, Wear D, Morrone CD, Yu WH. The complexity of extracellular vesicles: bridging the gap between cellular communication and neuropathology. J Neurochem 2024;168:2391-422.
129. Dutta S, Hornung S, Taha HB, Bitan G. Biomarkers for parkinsonian disorders in CNS-originating EVs: promise and challenges. Acta Neuropathol 2023;145:515-40.
130. Wiersema AF, Rennenberg A, Smith G, Varderidou-Minasian S, Pasterkamp RJ. Shared and distinct changes in the molecular cargo of extracellular vesicles in different neurodegenerative diseases. Cell Mol Life Sci 2024;81:479.
131. Danzer KM, Kranich LR, Ruf WP, et al. Exosomal cell-to-cell transmission of alpha synuclein oligomers. Mol Neurodegener 2012;7:42.
132. Emmanouilidou E, Melachroinou K, Roumeliotis T, et al. Cell-produced alpha-synuclein is secreted in a calcium-dependent manner by exosomes and impacts neuronal survival. J Neurosci 2010;30:6838-51.
133. Mavroeidi P, Vetsi M, Dionysopoulou D, Xilouri M. Exosomes in alpha-synucleinopathies: propagators of pathology or potential candidates for nanotherapeutics?. Biomolecules 2022;12:957.
134. Fussi N, Höllerhage M, Chakroun T, et al. Exosomal secretion of α-synuclein as protective mechanism after upstream blockage of macroautophagy. Cell Death Dis 2018;9:757.
135. Su X, Maguire-Zeiss KA, Giuliano R, Prifti L, Venkatesh K, Federoff HJ. Synuclein activates microglia in a model of Parkinson’s disease. Neurobiol Aging 2008;29:1690-701.
136. Gentzel RC, Toolan D, Jinn S, et al. Intracranial administration of alpha-synuclein fibrils in A30P-synuclein transgenic mice causes robust synucleinopathy and microglial induction. Neurobiol Aging 2021;106:12-25.
137. Bliederhaeuser C, Grozdanov V, Speidel A, et al. Age-dependent defects of alpha-synuclein oligomer uptake in microglia and monocytes. Acta Neuropathol 2016;131:379-91.
138. Pluvinage JV, Haney MS, Smith BAH, et al. CD22 blockade restores homeostatic microglial phagocytosis in ageing brains. Nature 2019;568:187-92.
139. Hallett PJ, Engelender S, Isacson O. Lipid and immune abnormalities causing age-dependent neurodegeneration and Parkinson’s disease. J Neuroinflammation 2019;16:153.
140. Jyothi HJ, Vidyadhara DJ, Mahadevan A, et al. Aging causes morphological alterations in astrocytes and microglia in human substantia nigra pars compacta. Neurobiol Aging 2015;36:3321-33.
141. Scheiblich H, Eikens F, Wischhof L, et al. Microglia rescue neurons from aggregate-induced neuronal dysfunction and death through tunneling nanotubes. Neuron 2024;112:3106-25.e8.
142. Bartels AL, Willemsen AT, Doorduin J, de Vries EF, Dierckx RA, Leenders KL. [11C]-PK11195 PET: quantification of neuroinflammation and a monitor of anti-inflammatory treatment in Parkinson’s disease?. Parkinsonism Relat Disord 2010;16:57-9.
143. Gerhard A, Pavese N, Hotton G, et al. In vivo imaging of microglial activation with [11C](R)-PK11195 PET in idiopathic Parkinson’s disease. Neurobiol Dis 2006;21:404-12.
144. Tansey MG, McCoy MK, Frank-Cannon TC. Neuroinflammatory mechanisms in Parkinson’s disease: potential environmental triggers, pathways, and targets for early therapeutic intervention. Exp Neurol 2007;208:1-25.
145. Surmeier DJ, Obeso JA, Halliday GM. Selective neuronal vulnerability in Parkinson disease. Nat Rev Neurosci 2017;18:101-13.
146. De Biase LM, Schuebel KE, Fusfeld ZH, et al. Local cues establish and maintain region-specific phenotypes of basal ganglia microglia. Neuron 2017;95:341-356.e6.
147. de Haas AH, Boddeke HW, Biber K. Region-specific expression of immunoregulatory proteins on microglia in the healthy CNS. Glia 2008;56:888-94.
148. Pocock JM, Kettenmann H. Neurotransmitter receptors on microglia. Trends Neurosci 2007;30:527-35.
149. Biber K, Neumann H, Inoue K, Boddeke HW. Neuronal ‘On’ and ‘Off’ signals control microglia. Trends Neurosci 2007;30:596-602.
150. Lee HJ, Suk JE, Patrick C, et al. Direct transfer of alpha-synuclein from neuron to astroglia causes inflammatory responses in synucleinopathies. J Biol Chem 2010;285:9262-72.
151. Yun SP, Kam TI, Panicker N, et al. Block of A1 astrocyte conversion by microglia is neuroprotective in models of Parkinson’s disease. Nat Med 2018;24:931-8.
152. Liddelow SA, Guttenplan KA, Clarke LE, et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature 2017;541:481-7.
153. Gu XL, Long CX, Sun L, Xie C, Lin X, Cai H. Astrocytic expression of Parkinson’s disease-related A53T alpha-synuclein causes neurodegeneration in mice. Mol Brain 2010;3:12.
154. Cavaliere F, Cerf L, Dehay B, et al. In vitro α-synuclein neurotoxicity and spreading among neurons and astrocytes using Lewy body extracts from Parkinson disease brains. Neurobiol Dis 2017;103:101-12.
155. Loria F, Vargas JY, Bousset L, et al. α-Synuclein transfer between neurons and astrocytes indicates that astrocytes play a role in degradation rather than in spreading. Acta Neuropathol 2017;134:789-808.
156. Chai H, Diaz-Castro B, Shigetomi E, et al. Neural circuit-specialized astrocytes: transcriptomic, proteomic, morphological, and functional evidence. Neuron 2017;95:531-49.e9.
157. Batiuk MY, Martirosyan A, Wahis J, et al. Identification of region-specific astrocyte subtypes at single cell resolution. Nat Commun 2020;11:1220.
158. Brandebura AN, Paumier A, Onur TS, Allen NJ. Astrocyte contribution to dysfunction, risk and progression in neurodegenerative disorders. Nat Rev Neurosci 2023;24:23-39.
159. Yang Y, Song JJ, Choi YR, et al. Therapeutic functions of astrocytes to treat α-synuclein pathology in Parkinson’s disease. Proc Natl Acad Sci U S A 2022;119:e2110746119.
160. Wise RM, Wagener A, Fietzek UM, et al. Interactions of dopamine, iron, and alpha-synuclein linked to dopaminergic neuron vulnerability in Parkinson’s disease and neurodegeneration with brain iron accumulation disorders. Neurobiol Dis 2022;175:105920.
162. Li WJ, Jiang H, Song N, Xie JX. Dose- and time-dependent alpha-synuclein aggregation induced by ferric iron in SK-N-SH cells. Neurosci Bull 2010;26:205-10.
163. Guo JJ, Yue F, Song DY, et al. Intranasal administration of α-synuclein preformed fibrils triggers microglial iron deposition in the substantia nigra of Macaca fascicularis. Cell Death Dis 2021;12:81.
164. Dexter DT, Carayon A, Javoy-Agid F, et al. Alterations in the levels of iron, ferritin and other trace metals in Parkinson’s disease and other neurodegenerative diseases affecting the basal ganglia. Brain 1991;114:1953-75.
165. Peralta C, Strafella AP, van Eimeren T, et al; International Parkinson Movement Disorders Society-Neuroimaging Study Group. Pragmatic approach on neuroimaging techniques for the differential diagnosis of parkinsonisms. Mov Disord Clin Pract. 2022;9:6-19
166. Alushaj E, Handfield-Jones N, Kuurstra A, et al. Increased iron in the substantia nigra pars compacta identifies patients with early Parkinson’s disease: a 3T and 7T MRI study. Neuroimage Clin 2024;41:103577.
167. Guan X, Guo T, Zhou C, et al. Altered brain iron depositions from aging to Parkinson’s disease and Alzheimer’s disease: a quantitative susceptibility mapping study. Neuroimage 2022;264:119683.
168. López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. Hallmarks of aging: an expanding universe. Cell 2023;186:243-78.
169. Hipp MS, Kasturi P, Hartl FU. The proteostasis network and its decline in ageing. Nat Rev Mol Cell Biol 2019;20:421-35.
170. Zalon AJ, Quiriconi DJ, Pitcairn C, Mazzulli JR. α-Synuclein: multiple pathogenic roles in trafficking and proteostasis pathways in Parkinson’s disease. Neuroscientist 2024;30:612-35.
171. Flores-Leon M, Outeiro TF. More than meets the eye in Parkinson’s disease and other synucleinopathies: from proteinopathy to lipidopathy. Acta Neuropathol 2023;146:369-85.
172. Liu Z, Huang Y, Wang X, et al. The cervical lymph node contributes to peripheral inflammation related to Parkinson’s disease. J Neuroinflammation 2023;20:93.
173. Terkelsen MH, Klaestrup IH, Hvingelby V, Lauritsen J, Pavese N, Romero-Ramos M. Neuroinflammation and immune changes in prodromal Parkinson’s disease and other synucleinopathies. J Parkinsons Dis 2022;12:S149-63.
174. Iba M, Kim C, Sallin M, et al. Neuroinflammation is associated with infiltration of T cells in Lewy body disease and α-synuclein transgenic models. J Neuroinflammation 2020;17:214.
175. Ren X, Hinchie A, Swomley A, Powell DK, Butterfield DA. Profiles of brain oxidative damage, ventricular alterations, and neurochemical metabolites in the striatum of PINK1 knockout rats as functions of age and gender: relevance to Parkinson disease. Free Radic Biol Med 2019;143:146-52.
176. Henrich MT, Geibl FF, Lakshminarasimhan H, et al. Determinants of seeding and spreading of α-synuclein pathology in the brain. Sci Adv 2020;6:eabc2487.
177. Brundin P, Melki R. Prying into the prion hypothesis for Parkinson’s disease. J Neurosci 2017;37:9808-18.
178. Guo JL, Covell DJ, Daniels JP, et al. Distinct α-synuclein strains differentially promote tau inclusions in neurons. Cell 2013;154:103-17.
179. He CL, Tang Y, Wu JM, et al. Chlorogenic acid delays the progression of Parkinson’s disease via autophagy induction in Caenorhabditis elegans. Nutr Neurosci 2023;26:11-24.
180. Tofaris GK. Initiation and progression of α-synuclein pathology in Parkinson’s disease. Cell Mol Life Sci 2022;79:210.
181. Galvagnion C, Buell AK, Meisl G, et al. Lipid vesicles trigger α-synuclein aggregation by stimulating primary nucleation. Nat Chem Biol 2015;11:229-34.
