Collaborators GBDPsD. Global, regional, and national burden of Parkinson’s disease, 1990–2016: a systematic analysis for the global burden of Disease Study 2016. Lancet Neurol. 2018;17:939–53.

Article  Google Scholar 

Jankovic J. Current concepts in Parkinson’s disease and other movement disorders. Curr Opin Neurol. 2012;25:429–32.

Article  PubMed  Google Scholar 

Taguchi K, Watanabe Y, Tsujimura A, Tanaka M. Brain region-dependent differential expression of alpha-synuclein. J Comp Neurol. 2016;524:1236–58.

Article  CAS  PubMed  Google Scholar 

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.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Moore DJ, West AB, Dawson VL, Dawson TM. Molecular pathophysiology of Parkinson’s disease. Annu Rev Neurosci. 2005;28:57–87.

Article  CAS  PubMed  Google Scholar 

Fauser M, Lohle M, Ebersbach G, Odin P, Fuchs G, Jost WH, Chaudhuri KR, Koch R. NoMoFlu PDsg, Storch A. Intraindividual variability of Nonmotor fluctuations in Advanced Parkinson’s Disease. J Parkinsons Dis. 2015;5:737–41.

Article  PubMed  Google Scholar 

Lewis SJ, Foltynie T, Blackwell AD, Robbins TW, Owen AM, Barker RA. Heterogeneity of Parkinson’s disease in the early clinical stages using a data driven approach. J Neurol Neurosurg Psychiatry. 2005;76:343–8.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Wolters E. Variability in the clinical expression of Parkinson’s disease. J Neurol Sci. 2008;266:197–203.

Article  PubMed  Google Scholar 

Greenland JC, Williams-Gray CH, Barker RA. The clinical heterogeneity of Parkinson’s disease and its therapeutic implications. Eur J Neurosci. 2019;49:328–38.

Article  PubMed  Google Scholar 

Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M. Alpha-synuclein in Lewy bodies. Nature. 1997;388:839–40.

Article  ADS  CAS  PubMed  Google Scholar 

Halliday GM, Holton JL, Revesz T, Dickson DW. Neuropathology underlying clinical variability in patients with synucleinopathies. Acta Neuropathol. 2011;122:187–204.

Article  CAS  PubMed  Google Scholar 

Jellinger KA. Formation and development of Lewy pathology: a critical update. J Neurol. 2009;256(Suppl 3):270–9.

Article  PubMed  Google Scholar 

Jensen PH, Schlossmacher MG, Stefanis L. Who Ever Said It Would Be Easy? Reflecting on Two Clinical Trials Targeting alpha-Synuclein. Mov Disord. 2023.

Sulzer D, Alcalay RN, Garretti F, Cote L, Kanter E, Agin-Liebes J, Liong C, McMurtrey C, Hildebrand WH, Mao X, Dawson VL, Dawson TM, Oseroff C, Pham J, Sidney J, Dillon MB, Carpenter C, Weiskopf D, Phillips E, Mallal S, Peters B, Frazier A, Lindestam Arlehamn CS, Sette A. T cells from patients with Parkinson’s disease recognize alpha-synuclein peptides. Nature. 2017;546:656–61.

Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

Maetzler W, Apel A, Langkamp M, Deuschle C, Dilger SS, Stirnkorb JG, Schulte C, Schleicher E, Gasser T, Berg D. Comparable autoantibody serum levels against amyloid- and inflammation-associated proteins in Parkinson’s disease patients and controls. PLoS ONE. 2014;9:e88604.

Article  ADS  PubMed  PubMed Central  Google Scholar 

Papachroni KK, Ninkina N, Papapanagiotou A, Hadjigeorgiou GM, Xiromerisiou G, Papadimitriou A, Kalofoutis A, Buchman VL. Autoantibodies to alpha-synuclein in inherited Parkinson’s disease. J Neurochem. 2007;101:749–56.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Kuhn I, Rogosch T, Schindler TI, Tackenberg B, Zemlin M, Maier RF, Dodel R, Kronimus Y. Serum titers of autoantibodies against alpha-synuclein and tau in child- and adulthood. J Neuroimmunol. 2018;315:33–9.

Article  CAS  PubMed  Google Scholar 

Patrias LM, Klaver AC, Coffey MP, Loeffler DA. Specific antibodies to soluble alpha-synuclein conformations in intravenous immunoglobulin preparations. Clin Exp Immunol. 2010;161:527–35.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Smith LM, Klaver AC, Coffey MP, Dang L, Loeffler DA. Effects of intravenous immunoglobulin on alpha synuclein aggregation and neurotoxicity. Int Immunopharmacol. 2012;14:550–7.

Article  CAS  PubMed  Google Scholar 

Pisani V, Stefani A, Pierantozzi M, Natoli S, Stanzione P, Franciotta D, Pisani A. Increased blood-cerebrospinal fluid transfer of albumin in advanced Parkinson’s disease. J Neuroinflammation. 2012;9:188.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Kortekaas R, Leenders KL, van Oostrom JC, Vaalburg W, Bart J, Willemsen AT, Hendrikse NH. Blood-brain barrier dysfunction in parkinsonian midbrain in vivo. Ann Neurol. 2005;57:176–9.

Article  CAS  PubMed  Google Scholar 

Orr CF, Rowe DB, Mizuno Y, Mori H, Halliday GM. A possible role for humoral immunity in the pathogenesis of Parkinson’s disease. Brain. 2005;128:2665–74.

Article  PubMed  Google Scholar 

Piepgras J, Holtje M, Otto C, Harms H, Satapathy A, Cesca F, Benfenati F, Gitler D, Pich A, Zander JF, Ahnert-Hilger G, Ruprecht K. Intrathecal immunoglobulin A and G antibodies to synapsin in a patient with limbic encephalitis. Neurol Neuroimmunol Neuroinflamm. 2015;2:e169.

Article  PubMed  PubMed Central  Google Scholar 

Lakos A, Ferenczi E, Komoly S, Granstrom M. Different B-cell populations are responsible for the peripheral and intrathecal antibody production in neuroborreliosis. Int Immunol. 2005;17:1631–7.

Article  CAS  PubMed  Google Scholar 

Mader S, Brimberg L, Diamond B. The role of brain-reactive autoantibodies in Brain Pathology and Cognitive Impairment. Front Immunol. 2017;8:1101.

Article  PubMed  PubMed Central  Google Scholar 

Li X, Koudstaal W, Fletcher L, Costa M, van Winsen M, Siregar B, Inganas H, Kim J, Keogh E, Macedo J, Holland T, Perry S, Bard F, Hoozemans JJ, Goudsmit J, Apetri A, Pascual G. Naturally occurring antibodies isolated from PD patients inhibit synuclein seeding in vitro and recognize Lewy pathology. Acta Neuropathol. 2019;137:825–36.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Braczynski AK, Sevenich M, Gering I, Kupreichyk T, Agerschou ED, Kronimus Y, Habib P, Stoldt M, Willbold D, Schulz JB, Bach JP, Falkenburger BH, Hoyer W. Alpha-synuclein-specific naturally occurring antibodies inhibit aggregation in Vitro and in vivo. Biomolecules. 2022;12.

Yu HJ, Thijssen E, van Brummelen E, van der Plas JL, Radanovic I, Moerland M, Hsieh E, Groeneveld GJ, Dodart JC. A Randomized First-in-human study with UB-312, a UBITh(R) alpha-synuclein peptide vaccine. Mov Disord. 2022;37:1416–24.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Garg P, Maass F, Sundaram SM, Mollenhauer B, Mahajani S, van Riesen C, Kügler S, Bähr M. The relevance of synuclein autoantibodies as a biomarker for Parkinson’s disease. Mol Cell Neurosci. 2022;121:103746.

Article  CAS  PubMed  Google Scholar 

Leite K, Garg P, Spitzner FP, Guerin Darvas S, Bähr M, Priesemann V, Kügler S. Alpha-synuclein impacts on intrinsic neuronal network activity through reduced levels of cyclic AMP and diminished numbers of active presynaptic terminals. Front Mol Neurosci. 2022;15:868790.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Tolo J, Taschenberger G, Leite K, Stahlberg MA, Spehlbrink G, Kues J, Munari F, Capaldi S, Becker S, Zweckstetter M, Dean C, Bähr M, Kügler S. Pathophysiological consequences of neuronal alpha-synuclein overexpression: impacts on Ion Homeostasis, stress signaling, mitochondrial Integrity, and Electrical Activity. Front Mol Neurosci. 2018;11:49.

Article  PubMed  PubMed Central  Google Scholar 

Nedergaard M, Ransom B, Goldman SA. New roles for astrocytes: redefining the functional architecture of the brain. Trends Neurosci. 2003;26:523–30.

Article  CAS  PubMed  Google Scholar 

Drinkut A, Tereshchenko Y, Schulz JB, Bähr M, Kügler S. Efficient gene therapy for Parkinson’s disease using astrocytes as hosts for localized neurotrophic factor delivery. Mol Ther. 2012;20:534–43.

Article  CAS  PubMed  Google Scholar 

Wilhelmsson U, Bushong EA, Price DL, Smarr BL, Phung V, Terada M, Ellisman MH, Pekny M. Redefining the concept of reactive astrocytes as cells that remain within their unique domains upon reaction to injury. Proc Natl Acad Sci U S A. 2006;103:17513–8.

Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

Sofroniew MV. Multiple roles for astrocytes as effectors of cytokines and inflammatory mediators. Neuroscientist. 2014;20:160–72.

Article  CAS  PubMed  Google Scholar 

Veldkamp CT, Koplinski CA, Jensen DR, Peterson FC, Smits KM, Smith BL, Johnson SK, Lettieri C, Buchholz WG, Solheim JC, Volkman BF. Production of recombinant chemokines and Validation of Refolding. Methods Enzymol. 2016;570:539–65.

Article