Cryo-EM structure of amyloid fibril formed by α-synuclein hereditary A53E mutation

Abstract

Synucleinopathies, including Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple systems atrophy (MSA) have the same hallmark pathologic feature of misfolded α-synuclein protein accumulation in the brain. PD patients who carry α-syn familial mutations usually have an earlier onset and more severe clinical symptoms and pathology than sporadic PD patients who carry wild-type (WT) α-syn. Therefore, revealing the structural effect of α-syn hereditary mutations on the wild-type fibril structure can help us understand synucleinopathies′ structural basis. Here, we present a 3.38 &Aring cryo-electron microscopy structure of α-synuclein fibrils containing the hereditary A53E mutation. The A53E fibril is composed of a symmetrical fibril, and the interaction interface between wild-type (WT) and A53E is different. In the mutant, only two residues, 59 and 60 form the interaction interface. Furthermore, ThT results and cell experiments also found that the A53E mutation delayed the formation of the fibril both in vitro and in vivo. This implies that the A53E mutation changes the aggregation mechanism of α-syn and therefore exhibits different pathological characteristics.