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  4. A NAC domain mutation (E83Q) unlocks the pathogenicity of human alpha-synuclein and recapitulates its pathological diversity
 
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research article

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

Kumar, Senthil T.
•
Mahul-Mellier, Anne-Laure  
•
Hegde, Ramanath Narayana  
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April 1, 2022
Science Advances

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 p5129, 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 immunohisto-chemical and morphological features of brainstem LBs observed in brains of patients with Parkinson's disease.

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Type
research article
DOI
10.1126/sciadv.abn0044
Web of Science ID

WOS:000790076700031

Author(s)
Kumar, Senthil T.
•
Mahul-Mellier, Anne-Laure  
•
Hegde, Ramanath Narayana  
•
Riviere, Gwladys
•
Moons, Rani
•
de Opakua, Alain Ibanez
•
Magalhaes, Pedro  
•
Rostami, Iman
•
Donzelli, Sonia  
•
Sobott, Frank
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Date Issued

2022-04-01

Publisher

AMER ASSOC ADVANCEMENT SCIENCE

Published in
Science Advances
Volume

8

Issue

17

Article Number

eabn0044

Subjects

Multidisciplinary Sciences

•

Science & Technology - Other Topics

•

lewy body pathology

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parkinsons-disease

•

bodies

•

aggregation

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inclusions

•

ubiquitin

•

dementia

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framework

•

proteins

•

affinity

Peer reviewed

REVIEWED

Written at

EPFL

EPFL units
LMNN  
Available on Infoscience
May 23, 2022
Use this identifier to reference this record
https://infoscience.epfl.ch/handle/20.500.14299/188088
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