Loss of monomeric alpha-synuclein (synucleinopenia) and the origin of Parkinson's disease.
Loss of monomeric alpha-synuclein (synucleinopenia) and the origin of Parkinson's disease.
Where did the research take place?
The study site has not been established. Author addresses may differ from where the research occurred.
Cincinnati, US · Author affiliation
James J. and Joan A. Gardner Family Center for Parkinson's Disease and Movement Disorders, Department of Neurology, University of Cincinnati, Cincinnati, OH, USA. Electronic address: alberto.espay@uc.edu.Location evidence
London, GB · Author affiliation
The National Hospital, Queen Square and Reta Lila Weston Institute for Neurological Studies University College London, London, UK.Location evidence
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Original abstract
These facts argue against the gain-of-function synucleinopathy hypothesis, which proposes that Lewy pathology causes Parkinson's disease: (1) most brains from people without neurological symptoms have multiple pathologies; (2) neither pathology type nor distribution correlate with disease severity or progression in Parkinson's disease; (3) aggregated α-synuclein in the form of Lewy bodies is not a space-occupying lesion but the insoluble fraction of its precursor, soluble monomeric α-synuclein; (4) pathology spread is passive, occurring by irreversible nucleation, not active replication; and (5) low cerebrospinal fluid α-synuclein levels predict brain atrophy and clinical disease progression. The transformation of α-synuclein into Lewy pathology may occur as a response to biological, toxic, or infectious stressors whose persistence perpetuates the nucleation process, depleting normal α-synuclein and eventually leading to Parkinson's symptoms from neuronal death. We propose testing the loss-of-function synucleinopenia hypothesis by evaluating the clinical and neurodegenerative rescue effect of replenishing the levels of monomeric α-synuclein.