Effects of the mutations Ala³⁰ to Pro and Ala⁵³ to Thr on the physical and morphological properties of α‐synuclein protein implicated in Parkinson's disease

TLDR

α‑Synuclein is linked to lesions in several neurodegenerative diseases, and mutations in its gene have been identified in families with inherited Parkinson’s disease. Wild‑type, Ala30Pro, and Ala53Thr α‑synuclein variants all self‑aggregate into amyloid‑like filaments, with the mutants producing more β‑sheet and mature filaments, indicating that insoluble amyloid deposits may drive neurodegeneration.

Abstract

α‐Synuclein (α‐syn) protein has been found in association with the pathological lesions of a number of neurodegenerative diseases. Recently, mutations in the α‐syn gene have been reported in families susceptible to an inherited form of Parkinson's disease. We report here that human wild‐type α‐syn, PD‐linked mutant α‐syn(Ala30Pro) and mutant α‐syn(Ala53Thr) proteins can self‐aggregate and form amyloid‐like filaments. The mutant α‐syn forms more β‐sheet and mature filaments than the wild‐type protein. These findings suggest that accumulation of α‐syn as insoluble deposits of amyloid may play a major role in the pathogenesis of these neurodegenerative diseases.