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

Peter Riederer*, Daniela Berg, Nicolas Casadei, Fubo Cheng, Joseph Classen, Christian Dresel, Wolfgang Jost, Rejko Krüger, Thomas Müller, Heinz Reichmann, Olaf Rieß, Alexander Storch, Sabrina Strobel, Thilo van Eimeren, Hans Ullrich Völker, Jürgen Winkler, Konstanze F. Winklhofer, Ullrich Wüllner, Friederike Zunke, Camelia Maria Monoranu

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

49 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)815-840
Number of pages26
JournalJournal of Neural Transmission
Volume126
Issue number7
DOIs
Publication statusPublished - 1 Jul 2019
Externally publishedYes

Keywords

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

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