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J Neural Transm (Vienna). 2019 Jul;126(7):815-840. doi: 10.1007/s00702-019-02025-9. Epub 2019 Jun 25.

α-Synuclein in Parkinson's disease: causal or bystander?

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Clinic and Policlinic for Psychiatry, Psychosomatics and Psychotherapy, University Hospital Würzburg, University of Würzburg, Margarete-Höppel-Platz 1, 97080, Würzburg, Germany.
Department of Psychiatry, University of South Denmark, Odense, Denmark.
Department of Neurology, UKHS, Christian-Albrechts-Universität, Campus Kiel, Kiel, Germany.
NGS Competence Center Tübingen, Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
Department of Neurology, University Hospital Leipzig, Leipzig, Germany.
Department of Neurology, Center for Movement Disorders, Neuroimaging Center Mainz, Clinical Neurophysiology, Forschungszentrum Translationale Neurowissenschaften (FTN), Rhein-Main-Neuronetz, Mainz, Germany.
Parkinson-Klinik Ortenau, Wolfach, Germany.
Clinical and Experimental Neuroscience, LCSB (Luxembourg Centre for Systems, Biomedicine), University of Luxembourg, Esch-sur-Alzette and Centre Hospitalier de Luxembourg (CHL), Luxembourg, Luxembourg.
National Center for Excellence in Research, Parkinson's disease (NCER-PD), Parkinson Research Clinic, Centre Hospitalier de Luxembourg, Luxembourg, Luxembourg.
Department of Neurology, Alexianer St. Joseph Berlin-Weißensee, Berlin, Germany.
Department of Neurology, University of Dresden, Dresden, Germany.
Institute of Medical Genetics and Applied Genomics, Tübingen, Germany.
Department of Neurology, University of Rostock, Rostock, Germany.
German Centre for Neurodegenerative Diseases (DZNE) Rostock/Greifswald, Rostock, Germany.
Department of Neuropathology, Institute of Pathology, University of Würzburg, Würzburg, Germany.
Department of Neurology, University Hospital of Cologne, Cologne, Germany.
Department of Pathology, Leopoldina Hospital, Schweinfurt, Germany.
Department Kopfkliniken, Molekulare Neurologie, Universitätsklinikum Erlangen, Erlangen, Germany.
Institute of Biochemistry and Pathobiochemistry, Ruhr-Universität Bochum, Bochum, Germany.
Department of Neurology, University of Bonn, German Center for Neurodegenerative Diseases (DZNE Bonn), Bonn, Germany.
Department of Biochemistry, Medical Faculty, University of Kiel, Kiel, Germany.


Parkinson's disease (PD) comprises a spectrum of disorders with differing subtypes, the vast majority of which share Lewy bodies (LB) as a characteristic pathological hallmark. The process(es) underlying LB generation and its causal trigger molecules are not yet fully understood. α-Synuclein (α-syn) is a major component of LB and SNCA gene missense mutations or duplications/triplications are causal for rare hereditary forms of PD. As typical sporadic PD is associated with LB pathology, a factor of major importance is the study of the α-syn protein and its pathology. α-Syn pathology is, however, also evident in multiple system atrophy (MSA) and Lewy body disease (LBD), making it non-specific for PD. In addition, there is an overlap of these α-synucleinopathies with other protein-misfolding diseases. It has been proven that α-syn, phosphorylated tau protein (pτ), amyloid beta (Aβ) and other proteins show synergistic effects in the underlying pathogenic mechanisms. Multiple cell death mechanisms can induce pathological protein-cascades, but this can also be a reverse process. This holds true for the early phases of the disease process and especially for the progression of PD. In conclusion, while rare SNCA gene mutations are causal for a minority of familial PD patients, in sporadic PD (where common SNCA polymorphisms are the most consistent genetic risk factor across populations worldwide, accounting for 95% of PD patients) α-syn pathology is an important feature. Conversely, with regard to the etiopathogenesis of α-synucleinopathies PD, MSA and LBD, α-syn is rather a bystander contributing to multiple neurodegenerative processes, which overlap in their composition and individual strength. Therapeutic developments aiming to impact on α-syn pathology should take this fact into consideration.


Autophagy; Gene expression; Lysosome; Neuroinflammation; Neuromelanin; Parkinson’s disease; Proteasome; Protein interactions; SNCA gene; Synucleinopathy; Therapy; α-Synuclein


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