alpha Synuclein control of mitochondrial homeostasis in human-derived neurons is disrupted by mutations associated with Parkinson's disease

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00159816%3A_____%2F17%3A00067089" target="_blank" >RIV/00159816:_____/17:00067089 - isvavai.cz</a>

Result on the web

<a href="http://dx.doi.org/10.1038/s41598-017-05334-9" target="_blank" >http://dx.doi.org/10.1038/s41598-017-05334-9</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1038/s41598-017-05334-9" target="_blank" >10.1038/s41598-017-05334-9</a>

Result language

angličtina

Original language name

alpha Synuclein control of mitochondrial homeostasis in human-derived neurons is disrupted by mutations associated with Parkinson's disease

Original language description

The etiology of Parkinson&apos;s disease (PD) converges on a common pathogenic pathway of mitochondrial defects in which alpha-Synuclein (alpha Syn) is thought to play a role. However, the mechanisms by which alpha Syn and its disease-associated allelic variants cause mitochondrial dysfunction remain unknown. Here, we analyzed mitochondrial axonal transport and morphology in human-derived neurons overexpressing wild-type (WT) alpha Syn or the mutated variants A30P or A53T, which are known to have differential lipid affinities. A53T alpha Syn was enriched in mitochondrial fractions, inducing significant mitochondrial transport defects and fragmentation, while milder defects were elicited by WT and A30P. We found that alpha Syn-mediated mitochondrial fragmentation was linked to expression levels in WT and A53T variants. Targeted delivery of WT and A53T alpha Syn to the outer mitochondrial membrane further increased fragmentation, whereas A30P did not. Genomic editing to disrupt the N-terminal domain of alpha Syn, which is important for membrane association, resulted in mitochondrial elongation without changes in fusion-fission protein levels, suggesting that alpha Syn plays a direct physiological role in mitochondrial size maintenance. Thus, we demonstrate that the association of alpha Syn with the mitochondria, which is modulated by protein mutation and dosage, influences mitochondrial transport and morphology, highlighting its relevance in a common pathway impaired in PD.

Czech name

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Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

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OECD FORD branch

30103 - Neurosciences (including psychophysiology)

Project

<a href="/en/project/EF15_003%2F0000492" target="_blank" >EF15_003/0000492: Unveiling the molecular determinants of agingto design new therapeutics</a><br>

Continuities

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Publication year

2017

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

Scientific Reports

ISSN

2045-2322

e-ISSN

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Volume of the periodical

7

Issue of the periodical within the volume

JUL

Country of publishing house

US - UNITED STATES

Number of pages

13

Pages from-to

5042

UT code for WoS article

000405172600009

EID of the result in the Scopus database

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