Fibril growth and seeding capacity play key roles in α-synuclein-mediated apoptotic cell death

A. L. Mahul-Mellier, F. Vercruysse, B. MacO, N. Ait-Bouziad, M. De Roo, D. Muller, H. A. Lashuel

Research output: Contribution to journalArticle

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Abstract

The role of extracellular α-synuclein (α-syn) in the initiation and the spreading of neurodegeneration in Parkinson's disease (PD) has been studied extensively over the past 10 years. However, the nature of the α-syn toxic species and the molecular mechanisms by which they may contribute to neuronal cell loss remain controversial. In this study, we show that fully characterized recombinant monomeric, fibrillar or stabilized forms of oligomeric α-syn do not trigger significant cell death when added individually to neuroblastoma cell lines. However, a mixture of preformed fibrils (PFFs) with monomeric α-syn becomes toxic under conditions that promote their growth and amyloid formation. In hippocampal primary neurons and ex vivo hippocampal slice cultures, α-syn PFFs are capable of inducing a moderate toxicity over time that is greatly exacerbated upon promoting fibril growth by addition of monomeric α-syn. The causal relationship between α-syn aggregation and cellular toxicity was further investigated by assessing the effect of inhibiting fibrillization on α-syn-induced cell death. Remarkably, our data show that blocking fibril growth by treatment with known pharmacological inhibitor of α-syn fibrillization (Tolcapone) or replacing monomeric α-syn by monomeric β-synuclein in α-syn mixture composition prevent α-syn-induced toxicity in both neuroblastoma cell lines and hippocampal primary neurons. We demonstrate that exogenously added α-syn fibrils bind to the plasma membrane and serve as nucleation sites for the formation of α-syn fibrils and promote the accumulation and internalization of these aggregates that in turn activate both the extrinsic and intrinsic apoptotic cell death pathways in our cellular models. Our results support the hypothesis that ongoing aggregation and fibrillization of extracellular α-syn play central roles in α-syn extracellular toxicity, and suggest that inhibiting fibril growth and seeding capacity constitute a viable strategy for protecting against α-syn-induced toxicity and slowing the progression of neurodegeneration in PD and other synucleinopathies.

Original languageEnglish
Pages (from-to)2107-2122
Number of pages16
JournalCell Death and Differentiation
Volume22
Issue number12
DOIs
Publication statusPublished - 1 Dec 2015
Externally publishedYes

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Synucleins
Cell Death
Poisons
Growth
Neuroblastoma
Parkinson Disease
Neurons
Cell Line
Amyloid
Cell Membrane
Pharmacology

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

Cite this

Mahul-Mellier, A. L., Vercruysse, F., MacO, B., Ait-Bouziad, N., De Roo, M., Muller, D., & Lashuel, H. A. (2015). Fibril growth and seeding capacity play key roles in α-synuclein-mediated apoptotic cell death. Cell Death and Differentiation, 22(12), 2107-2122. https://doi.org/10.1038/cdd.2015.79

Fibril growth and seeding capacity play key roles in α-synuclein-mediated apoptotic cell death. / Mahul-Mellier, A. L.; Vercruysse, F.; MacO, B.; Ait-Bouziad, N.; De Roo, M.; Muller, D.; Lashuel, H. A.

In: Cell Death and Differentiation, Vol. 22, No. 12, 01.12.2015, p. 2107-2122.

Research output: Contribution to journalArticle

Mahul-Mellier, AL, Vercruysse, F, MacO, B, Ait-Bouziad, N, De Roo, M, Muller, D & Lashuel, HA 2015, 'Fibril growth and seeding capacity play key roles in α-synuclein-mediated apoptotic cell death', Cell Death and Differentiation, vol. 22, no. 12, pp. 2107-2122. https://doi.org/10.1038/cdd.2015.79
Mahul-Mellier AL, Vercruysse F, MacO B, Ait-Bouziad N, De Roo M, Muller D et al. Fibril growth and seeding capacity play key roles in α-synuclein-mediated apoptotic cell death. Cell Death and Differentiation. 2015 Dec 1;22(12):2107-2122. https://doi.org/10.1038/cdd.2015.79
Mahul-Mellier, A. L. ; Vercruysse, F. ; MacO, B. ; Ait-Bouziad, N. ; De Roo, M. ; Muller, D. ; Lashuel, H. A. / Fibril growth and seeding capacity play key roles in α-synuclein-mediated apoptotic cell death. In: Cell Death and Differentiation. 2015 ; Vol. 22, No. 12. pp. 2107-2122.
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