{Reference Type}: Journal Article
{Title}: Loss of monomeric alpha-synuclein (synucleinopenia) and the origin of Parkinson's disease.
{Author}: Espay AJ;Lees AJ;
{Journal}: Parkinsonism Relat Disord
{Volume}: 122
{Issue}: 0
{Year}: 2024 May 3
{Factor}: 4.402
{DOI}: 10.1016/j.parkreldis.2024.106077
{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.