A novel mutation (E83Q) unlocks the pathogenicity of human alpha-synuclein fibrils and recapitulates its pathological diversity

Kumar, S. T.; Mahul-Mellier, A.-L.; Hegde, R. N.; Moons, R.; Magalhaes, P.; Ibanez de Opakua, A.; Riviere, G.; Rostami, I.; Donzelli, S.; Zweckstetter, M.; Sobott, F.; Lashuel, H. A.

doi:10.1101/2021.11.21.469421

bioRxiv · 10.1101/2021.11.21.469421

A novel mutation (E83Q) unlocks the pathogenicity of human alpha-synuclein fibrils and recapitulates its pathological diversity

Kumar, S. T.·Mahul-Mellier, A.-L.·Hegde, R. N.·Moons, R.·Magalhaes, P.·Ibanez de Opakua, A.·Riviere, G.·Rostami, I.·Donzelli, S.·Zweckstetter, M.·Sobott, F.·Lashuel, H. A.

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Abstract

A novel mutation (E83Q), the first in the NAC domain of alpha-synuclein (aSyn), was recently identified in a patient with dementia with Lewy bodies. We investigated the effects of this mutation on the aggregation of aSyn monomers and the structure, morphology, dynamic, and seeding activity of the aSyn fibrils in neurons. We found that it dramatically accelerates aSyn fibrillization and results in the formation of fibrils with distinct structural and dynamic properties. In cells, this mutation is associated with higher levels of aSyn, accumulation of pS129, and increased toxicity. In a neuronal seeding model of Lewy bodies (LB) formation, the E83Q mutation significantly enhances the internalization of fibrils into neurons, induce higher seeding activity and results in the formation of diverse aSyn pathologies, including the formation of LB-like inclusions that recapitulate the immunohistochemical and morphological features of brainstem LBs observed in PD patient brains. TeaserA novel mutation (E83Q) exacerbates alpha-synuclein aggregation and toxicity and reproduces PD pathological diversity.

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Kumar, S. T., Mahul-Mellier, A.-L., Hegde, R. N., Moons, R., Magalhaes, P., Ibanez de Opakua, A., Riviere, G., Rostami, I., Donzelli, S., Zweckstetter, M., Sobott, F., Lashuel, H. A.. 2021-11-21. A novel mutation (E83Q) unlocks the pathogenicity of human alpha-synuclein fibrils and recapitulates its pathological diversity. https://doi.org/10.1101/2021.11.21.469421

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