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

Mohamed Bilal Fares, Bohumil Maco, Abid Oueslati, Edward Rockenstein, Natalia Ninkina, Vladimir L. Buchman, Eliezer Masliah, Hilal A. Lashuel

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

Lewy bodies (LBs) are intraneuronal inclusions consisting primarily of fibrillized human a-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.

Original languageEnglish
Pages (from-to)E912-E921
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number7
DOIs
Publication statusPublished - 16 Feb 2016

Fingerprint

Synucleins
Parkinson Disease
Lewy Bodies
Pathology
Neurons
Fluorescence Recovery After Photobleaching
Genetic Testing
Ubiquitin
Electron Microscopy
Proteins

Keywords

  • Aggregation
  • Alpha-synuclein
  • Parkinson's disease

ASJC Scopus subject areas

  • General

Cite this

Induction of de novo a-synuclein fibrillization in a neuronal model for Parkinson's disease. / Fares, Mohamed Bilal; Maco, Bohumil; Oueslati, Abid; Rockenstein, Edward; Ninkina, Natalia; Buchman, Vladimir L.; Masliah, Eliezer; Lashuel, Hilal A.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 113, No. 7, 16.02.2016, p. E912-E921.

Research output: Contribution to journalArticle

Fares, MB, Maco, B, Oueslati, A, Rockenstein, E, Ninkina, N, Buchman, VL, Masliah, E & Lashuel, HA 2016, 'Induction of de novo a-synuclein fibrillization in a neuronal model for Parkinson's disease', Proceedings of the National Academy of Sciences of the United States of America, vol. 113, no. 7, pp. E912-E921. https://doi.org/10.1073/pnas.1512876113
Fares, Mohamed Bilal ; Maco, Bohumil ; Oueslati, Abid ; Rockenstein, Edward ; Ninkina, Natalia ; Buchman, Vladimir L. ; Masliah, Eliezer ; Lashuel, Hilal A. / Induction of de novo a-synuclein fibrillization in a neuronal model for Parkinson's disease. In: Proceedings of the National Academy of Sciences of the United States of America. 2016 ; Vol. 113, No. 7. pp. E912-E921.
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