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

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.

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(modified from Ruf et al. 2008)

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Acknowledgements

PR is thankful to the “Verein zur Durchführung neurowissenschaftlicher Tagungen e. V.” for supporting this work.

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Riederer, P., Berg, D., Casadei, N. et al. α-Synuclein in Parkinson’s disease: causal or bystander?. J Neural Transm 126, 815–840 (2019). https://doi.org/10.1007/s00702-019-02025-9

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Keywords

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