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

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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

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Keywords

  • Aggregation
  • Alpha-synuclein
  • Parkinson's disease

ASJC Scopus subject areas

  • General

Cite this

Fares, M. B., Maco, B., Oueslati, A., Rockenstein, E., Ninkina, N., Buchman, V. L., Masliah, E., & Lashuel, H. A. (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, 113(7), E912-E921. https://doi.org/10.1073/pnas.1512876113