In the May 27 Nature, scientists publish the first-ever cryo-electron microscopy of α-synuclein fibrils. With resolution down to the atomic level, the analysis revealed two types of asymmetric fibril, each comprising two different protofibrils. The three-dimensional structures look nothing like those formed by Aβ or tau fibrils, or indeed by fibrils made in the lab from recombinant α-synuclein.
α-Synuclein structures will help scientists understand how the protein aggregates, and they will provide templates for designing PET ligands that can detect the fibrils in living people.
Michel Goedert, from the MRC Laboratory of Molecular Biology, Cambridge, U.K., and a senior author on the paper, presented the structures at the Tau2020 meeting in Washington, D.C., last March (Mar 2020 conference news).
Synuclein Asymmetry. Two types of α-synuclein fibril were found in the brains of MSA patients. Type II (shown) comprises two types of protofilament. PF-IIA was similar to PF-IA in type I fibrils. The second protofilament came in two forms, PF-IIB1 and PF-IIB2. PF-IIB is smaller than the PF-IB of type I filaments. [Courtesy of Schweighauser et al., Nature.]
Goedert collaborated on the project with co-senior authors Sjors Scheres, also at the MRC, and Masato Hasegawa at the Tokyo Metropolitan Institute of Medical Science. Co-first authors Manuel Schweighauser and Yang Shi at the MRC isolated α-synuclein fibrils postmortem from five people who had died with multiple-system atrophy, a synucleinopathy that mostly attacks glial cells. Three of the volunteers had lived with the disease for about nine to 10 years, and they had mostly type I fibrils in their putamen. The other two lived with MSA for 18 and 19 years and had mostly type II fibrils in the same region. “This suggests that the duration of MSA may correlate with the ratio of filament types in putamen, but additional cases of disease are required to establish this more firmly,” note the authors.
The type of fibril differed by brain region, as well. Of three patients with predominantly type I filaments in the putamen, one had mostly type II in the cerebellum, while the other two had mostly type II in the cortex. It is unclear whether the two types are just as unequally distributed among nerve and glial cells, or how that relates to brain region.
Another surprising phenomenon is that, in the fibril cores (see image above), the protofibrils make much more extensive contact with each other than do protofibrils in Aβ or tau fibrils (Jul 2017 news; Sep 2017 news). Because the α-synuclein protofilament axis tilts with respect to the fibril axis, each protofilament monomer contacts three monomers in the opposing protofilament (see image below). How this affects aggregation dynamics and stability remains to be determined.
Protofibril Troika. Each synuclein protofilament monomer touches three in the opposing chain. The N terminus of the green PF-IB contacts the C terminus of the faded red PF-IA one up the chain. The C terminus of the green PF-IB binds the N terminus of the faded blue PF-IA one down the chain. [Courtesy of Schweighauser et al., 2020, Nature.]
Do similar fibrils explain other synucleinopathies, such as Parkinson’s and dementia with Lewy bodies? Apparently not. The authors also isolated fibrils from people who had DLB. These lacked the characteristic twist of MSA fibrils, which precluded cryoEM analysis. However, based on two-dimensional analysis, these structures are different.
For details on how the new structures relate to pathogenic mutations, and on a curious nonprotein cavity in the fibril cores, see our March conference news.—Tom Fagan
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- Schweighauser M, Shi Y, Tarutani A, Kametani F, Murzin AG, Ghetti B, Matsubara T, Tomita T, Ando T, Hasegawa K, Murayama S, Yoshida M, Hasegawa M, Scheres SH, Goedert M. Structures of α-synuclein filaments from multiple system atrophy. Nature. 2020 Sep;585(7825):464-469. Epub 2020 May 27 PubMed.