2022-04-29 スイス連邦工科大学ローザンヌ校(EPFL)
科学者たちは、シヌクレインパチーを引き起こすアルファシヌクレイン遺伝子の多くの変異を同定し、マップを作成してきました。ラシュエル研究室を含む多くの研究が、変異が異なるメカニズムで作用し、同じ病態を引き起こす可能性もあることを明らかにしています。まれではありますが、これらの変異の研究は重要な洞察につながり、神経変性やパーキンソン病の発症に寄与するさまざまなメカニズムの解明に役立っています。
<関連情報>
- https://actu.epfl.ch/news/a-new-mutation-behind-synucleinopathies/
- https://www.science.org/doi/10.1126/sciadv.abn0044
NACドメイン変異(E83Q)がヒトαシヌクレインの病原性を解き明かし、その病態の多様性を再現する A NAC domain mutation (E83Q) unlocks the pathogenicity of human alpha-synuclein and recapitulates its pathological diversity
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 AND HILAL A. LASHUEL
Science Advances Published:29 Apr 2022
DOI: 10.1126/sciadv.abn0044
Abstract
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.
