A NAC domain mutation (E83Q) unlocks the pathogenicity of human alpha-synuclein and recapitulates its pathological diversity
| Autor: | Senthil T. Kumar, Anne-Laure Mahul-Mellier, Ramanath Narayana Hegde, Gwladys Rivière, Rani Moons, Alain Ibáñez de Opakua, Pedro Magalhães, Iman Rostami, Sonia Donzelli, Frank Sobott, Markus Zweckstetter, Hilal A. Lashuel |
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| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: |
pathology [Lewy Bodies]
Multidisciplinary Virulence inclusions education metabolism [Parkinson Disease] aggregation Parkinson Disease metabolism [Lewy Bodies] proteins bodies framework ubiquitin Mutation genetics [alpha-Synuclein] alpha-Synuclein Humans parkinsons-disease affinity Lewy Bodies ddc:500 Human medicine chemistry [Lewy Bodies] lewy body pathology dementia |
| Zdroj: | Science Advances Science advances 8(17), eabn0044 (2022). doi:10.1126/sciadv.abn0044 |
| ISSN: | 2375-2548 |
| DOI: | 10.1126/sciadv.abn0044 |
| Popis: | The alpha-synuclein mutation E83Q, the first in the NAC domain of the protein, 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 markedly 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 body (LB) formation, the E83Q mutation significantly enhances the internalization of fibrils into neurons, induces 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 brains of patients with Parkinson’s disease. |
| Databáze: | OpenAIRE |
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