Research progress on E46K mutation of α-synuclein exacerbating pathological condition of Parkinson's disease

Parkinson's disease (PD) is a neurodegenerative disorder characterized by bradykinesia, tremor and rigidity. The neuropathological features of PD are progressive loss of dopaminergic neurons and abnormal aggregation of α-synuclein (α-syn)to form Lewy bodies. Among the known PD pathogenic gene mutations, the E46K mutation of the α-synuclein SNCA gene has attracted much attention due to its unique pathological mechanism and significant clinical phenotype. Compared with other common mutations(such as A53T, A30P), the E46K mutation not only significantly enhances the oligomerization and fibrosis tendency of α-syn by changing the electrostatic interaction and spatial conformation of α-syn, but also promotes the formation of more stable β-sheet structure, resulting in more neurotoxic aggregates. More importantly, E46K mutation carriers show earlier age of onset, faster disease progression, and more severe behavioral disorders. This article systematically summarizes the research progress of the unique molecular mechanism and pathological characteristics of E46 Kα-syn mutation in PD, in order to further clarify the pathogenesis and development of PD.