Sequence- and seed-structure-dependent polymorphic fibrils of alpha-synuclein

Biochimica Et Biophysica Acta. Molecular Basis of Disease
Goki TanakaNobuyuki Nukina

Abstract

Synucleinopathies comprise a diverse group of neurodegenerative diseases including Parkinson's disease (PD), dementia with Lewy bodies, and multiple system atrophy. These share a common pathological feature, the deposition of alpha-synuclein (a-syn) in neurons or oligodendroglia. A-syn is highly conserved in vertebrates, but the primary sequence of mouse a-syn differs from that of human at seven positions. However, structural differences of their aggregates remain to be fully characterized. In this study, we found that human and mouse a-syn aggregated in vitro formed morphologically distinct amyloid fibrils exhibiting twisted and straight structures, respectively. Furthermore, we identified different protease-resistant core regions, long and short, in human and mouse a-syn aggregates. Interestingly, among the seven unconserved amino acids, only A53T substitution, one of the familial PD mutations, was responsible for structural conversion to the straight-type. Finally, we checked whether the structural differences are transmissible by seeding and found that human a-syn seeded with A53T aggregates formed straight-type fibrils with short protease-resistant cores. These results suggest that a-syn aggregates form sequence-dependent ...Continue Reading

Citations

Sep 19, 2019·Cellular and Molecular Life Sciences : CMLS·Ye TianZhentao Zhang
Sep 10, 2020·Molecular Neurodegeneration·Natalie LandeckJean-Christophe Rochet
Apr 30, 2021·Frontiers in Molecular Neuroscience·Blagovesta PopovaGerhard H Braus
Jan 19, 2022·Movement Disorders : Official Journal of the Movement Disorder Society·Morgane LinardCatherine Helmer

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