Protein Coaggregation in Caribbean Atypical Parkinsonism: The Contribution of Annonacin.

AIMS: There is an unexpectedly high proportion of atypical forms of degenerative parkinsonism in the French Caribbean islands. Residents of these islands are thought to be susceptible to Caribbean atypical parkinsonism (CAP) owing to their consumption of Annonaceae plant products containing the mitochondrial toxin annonacin. Here, we aimed to better correlate the clinical diagnosis of CAP with the misfolded protein pathology observed in affected individuals and to further investigate how annonacin could contribute to CAP pathogenesis. METHODS: We conducted postmortem histopathological analysis of brain samples from eight patients; more specifically, we assessed the distribution and burden of α-synuclein (αS) and tau pathologies. Additionally, we studied how annonacin influences αS and tau aggregation using biophysical assays, with the corresponding recombinant human proteins serving as substrates. RESULTS: CAP was associated with heterogeneous clinical and histopathological features. Tau/αS copathology with a predominance of either αS or tau aggregates was observed in the majority (5/8) of patients. Tau and αS aggregates were sometimes colocalised in the same brain regions or cells. In biophysical assays, we showed that annonacin leads to an increase in αS aggregation and the formation of αS fibrils that could cross-seed tau aggregation. CONCLUSIONS: Annonacin may contribute to degenerative CAP by modulating the production of tau and αS pathogenic protein assemblies.