PT  - JOURNAL ARTICLE
AU  - Chuanqi Sun
AU  - Kang Zhou
AU  - Peter DePaola IV
AU  - Woo Shik Shin
AU  - Trae Hillyer
AU  - Michael R. Sawaya
AU  - Z. Hong Zhou
AU  - Lin Jiang
TI  - Cryo-EM structure of amyloid fibril formed by α-synuclein hereditary A53E mutation
AID  - 10.1101/2022.03.11.483992
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2022.03.11.483992
4099  - http://biorxiv.org/content/early/2022/03/30/2022.03.11.483992.short
4100  - http://biorxiv.org/content/early/2022/03/30/2022.03.11.483992.full
AB  - 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 hereditary mutations tend to 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 Å cryo-electron microscopy structure of α-synuclein fibrils containing the hereditary A53E mutation. The A53E fibril is symmetrically composed of two protofilaments, as are many other synucleopathic structures – including WT. Interestingly, the interface between the protofilaments in A53E has significantly less buried surface area than all other documented fibril structures of α-syn and its other mutants. The A53E fibril also exhibits slower formation/growth in in vitro fibrillation experiment compared to other mutants. This implies that the structural differences - both in the protofilament and between each protofilament of A53E – change the aggregation mechanism, or in the least, its kinetics of formation. These differences influence the molecular characteristics of each fibril mutant and likely plays a macro-scale role in progressing one clinical pathology over another.Competing Interest StatementThe authors have declared no competing interest.