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

Kód výsledku v 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>

Výsledek na webu

<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>

Jazyk výsledku

angličtina

Název v původním jazyce

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

Popis výsledku v původním jazyce

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.

Název v anglickém jazyce

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

Popis výsledku anglicky

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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30103 - Neurosciences (including psychophysiology)

Projekt

<a href="/cs/project/EF15_003%2F0000492" target="_blank" >EF15_003/0000492: Mapování molekulární podstaty procesů stárnutí pro vývoj nových léčebných metod</a><br>

Návaznosti

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

Rok uplatnění

2017

Kód důvěrnosti údajů

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

Název periodika

Scientific Reports

ISSN

2045-2322

e-ISSN

—

Svazek periodika

7

Číslo periodika v rámci svazku

JUL

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

13

Strana od-do

5042

Kód UT WoS článku

000405172600009

EID výsledku v databázi Scopus

—