Amyloid deposition of α-synuclein (α-syn) is a hallmark of Parkinson’s disease (PD). α-Syn fibrillation and cell-to-cell transmission in the brain play an essential role in disease progression. Up to date, eight single-point mutations of SNCA have been identified in familial PD (fPD), which feature early-onset, severe and highly heterogeneous clinical symptoms.

  

Previously, Prof. Liu’s group revealed that α-syn mutations including E46K, A53T form different fibril structures that are distinct from wild-type (WT) α-syn fibrils. Whether and how hereditary mutations-induced fibril polymorphism contributes to the early-onset and exacerbated pathology in fPD remains to be elucidated. More importantly, most fPD patients are heterozygous for SNCA mutations, which leads to another critical question: could mutant fibrils cross-seed WT α-syn to orchestrate neuropathology in fPD patients?

 

On May 11th, 2021, a research paper titled “Wild-type α-synuclein inherits the structure and exacerbated neuropathology of E46K mutant fibril strain by cross-seeding” was published on the Proceedings of the National Academy of Sciences of the United States of America journal by Prof. Cong Liu and Prof. Kaiwen He groups from the Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences. In this paper, the researchers reveal the structural basis underlying the cross-seeding between the WT and fPD mutant α-syn, underscore the importance of fibril structure in determining α-syn neuropathology, and provide mechanistic understanding for the pathology of E46K-associated fPD.

 

In this study, the researchers found that human E46K (hE46K) and human WT (hWT) fibril strains induced α-syn aggregates with distinct morphologies in mice brain. Mice injected with the hE46K strain induced more endogenous α-syn aggregation and early-onset motor deficits compared to the mice injected with the hWT strain. Notably, the hE46K fibril cross-seeded hWT α-syn, and induce hWT to formed hWTcs fibril stain which replicated the structure and seeding capability of the hE46K template both in vitro and in vivo. These results suggest that the E46K fibril could propagate its structure as well as the seeding properties to the WT monomer so as to amplify the α-syn pathology in fPD (Fig. 1). This work suggests that the structural and pathological features of mutant strains could be propagated by the WT α-syn in such a way that the mutant pathology would be amplified in fPD.

 

 

Fig.1 Schematic summary of the exacerbated α-syn neuropathology in heterozygous familial PD

 

The co-corresponding authors are Prof. Cong Liu and Prof. Kaiwen He from the Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences. Gratulate students Houfang Long (Liu lab) and Weitong Zheng (He lab) are the co-first authors. This work was supported by the Major State Basic Research Development Program, the National Natural Science Foundation of China, the Science and Technology Commission of Shanghai Municipality and so on. The cryo-electron microscopy (cryo-EM) platform of Peking University provides facility supports in cryo-EM.

 

 

Liu Cong Ph.D. Professor

Tel: 021-68582528

Email: liulab@sioc.ac.cn