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  4. Induction of de novo α-synuclein fibrillization in a neuronal model for Parkinson's disease
 
research article

Induction of de novo α-synuclein fibrillization in a neuronal model for Parkinson's disease

Fares, Mohamed-Bilal  
•
Maco, Bohumil  
•
Oueslati, Abid  
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2016
Proceedings Of The National Academy Of Sciences Of The United States Of America (PNAS)

Lewy bodies (LBs) are intraneuronal inclusions consisting primarily of fibrillized human α-synuclein (hα-Syn) protein, which represent the major pathological hallmark of Parkinson's disease (PD). Although doubling hα-Syn expression provokes LB pathology in humans, hα-Syn overexpression does not trigger the formation of fibrillar LB-like inclusions in mice. We hypothesized that interactions between exogenous hα-Syn and endogenous mouse synuclein homologs could be attenuating hα-Syn fibrillization in mice, and therefore, we systematically assessed hα-Syn aggregation propensity in neurons derived from α-Syn-KO, β-Syn-KO, γ-Syn-KO, and triple-KO mice lacking expression of all three synuclein homologs. Herein, we show that hα-Syn forms hyperphosphorylated (at S129) and ubiquitin-positive LB-like inclusions in primary neurons of α-Syn-KO, β-Syn-KO, and triple-KO mice, as well as in transgenic α-Syn-KO mouse brains in vivo. Importantly, correlative light and electron microscopy, immunogold labeling, and thioflavin-S binding established their fibrillar ultrastructure, and fluorescence recovery after photobleaching/photoconversion experiments showed that these inclusions grow in size and incorporate soluble proteins. We further investigated whether the presence of homologous α-Syn species would interfere with the seeding and spreading of α-Syn pathology. Our results are in line with increasing evidence demonstrating that the spreading of α-Syn pathology is most prominent when the injected preformed fibrils and host-expressed α-Syn monomers are from the same species. These findings provide insights that will help advance the development of neuronal and in vivo models for understanding mechanisms underlying hα-Syn intraneuronal fibrillization and its contribution to PD pathogenesis, and for screening pharmacologic and genetic modulators of α-Syn fibrillization in neurons.

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Type
research article
DOI
10.1073/pnas.1512876113
Web of Science ID

WOS:000370220000015

Author(s)
Fares, Mohamed-Bilal  
Maco, Bohumil  
Oueslati, Abid  
Rockenstein, Edward
Ninkina, Natalia
Buchman, Vladimir L
Masliah, Eliezer
Lashuel, Hilal A  
Date Issued

2016

Publisher

Natl Acad Sciences

Published in
Proceedings Of The National Academy Of Sciences Of The United States Of America (PNAS)
Volume

113

Issue

7

Start page

E912

End page

21

Subjects

Parkinson's disease

•

alpha-synuclein

•

aggregation

Editorial or Peer reviewed

NON-REVIEWED

Written at

EPFL

EPFL units
LMNN  
Available on Infoscience
March 4, 2016
Use this identifier to reference this record
https://infoscience.epfl.ch/handle/20.500.14299/124596
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