Reducing C-terminal truncation mitigates synucleinopathy and neurodegeneration in a transgenic model of multiple system atrophy

Fares Bassil, Pierre Olivier Fernagut, Erwan Bezard, Alain Pruvost, Thierry Leste-Lasserre, Quyen Hoang, Dagmar Ringe, Gregory A. Petsko, Wassilios G. Meissner

Research output: Contribution to journalArticle

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Abstract

Multiple system atrophy (MSA) is a sporadic orphan neurodegenerative disorder. No treatment is currently available to slow down the aggressive neurodegenerative process, and patients die within a few years after disease onset. The cytopathological hallmark of MSA is the accumulation of alpha-synuclein (α-syn) aggregates in affected oligodendrocytes. Several studies point to α-syn oligomerization and aggregation as a mediator of neurotoxicity in synucleinopathies including MSA. C-terminal truncation by the inflammatory protease caspase-1 has recently been implicated in the mechanisms that promote aggregation of α-syn in vitro and in neuronal cell models of α-syn toxicity. We present here an in vivo proof of concept of the ability of the caspase-1 inhibitor prodrug VX-765 to mitigate α-syn pathology and to mediate neuroprotection in proteolipid protein α-syn (PLP-SYN) mice, a transgenic mouse model of MSA. PLP-SYN and age-matched wild-type mice were treated for a period of 11 wk with VX-765 or placebo. VX-765 prevented motor deficits in PLP-SYN mice compared with placebo controls. More importantly, VX-765 was able to limit the progressive toxicity of α-syn aggregation by reducing its load in the striatum of PLP-SYN mice. Not only did VX-765 reduce truncated α-syn, but it also decreased its monomeric and oligomeric forms. Finally, VX-765 showed neuroprotective effects by preserving tyrosine hydroxylase-positive neurons in the substantia nigra of PLP-SYN mice. In conclusion, our results suggest that VX-765, a drug that was well tolerated in a 6 wk-long phase II trial in patients with epilepsy, is a promising candidate to achieve disease modification in synucleinopathies by limiting α-syn accumulation.

Original languageEnglish (US)
Pages (from-to)9593-9598
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number34
DOIs
StatePublished - Aug 23 2016

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Multiple System Atrophy
Proteolipids
Proteins
Placebos
Caspase 1
alpha-Synuclein
Orphaned Children
Oligodendroglia
Prodrugs
Tyrosine 3-Monooxygenase
Neuroprotective Agents
Substantia Nigra
1-(2-((1-(4-amino-3-chlorophenyl)methanoyl)amino)-3,3-dimethylbutanoyl)pyrrolidine-2-carboxylic acid
Neurodegenerative Diseases
Transgenic Mice
Epilepsy
Peptide Hydrolases
Pathology
Neurons
Pharmaceutical Preparations

Keywords

  • Alpha-synuclein
  • Caspase-1
  • Multiple system atrophy
  • Truncation

ASJC Scopus subject areas

  • General

Cite this

Reducing C-terminal truncation mitigates synucleinopathy and neurodegeneration in a transgenic model of multiple system atrophy. / Bassil, Fares; Fernagut, Pierre Olivier; Bezard, Erwan; Pruvost, Alain; Leste-Lasserre, Thierry; Hoang, Quyen; Ringe, Dagmar; Petsko, Gregory A.; Meissner, Wassilios G.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 113, No. 34, 23.08.2016, p. 9593-9598.

Research output: Contribution to journalArticle

Bassil, Fares ; Fernagut, Pierre Olivier ; Bezard, Erwan ; Pruvost, Alain ; Leste-Lasserre, Thierry ; Hoang, Quyen ; Ringe, Dagmar ; Petsko, Gregory A. ; Meissner, Wassilios G. / Reducing C-terminal truncation mitigates synucleinopathy and neurodegeneration in a transgenic model of multiple system atrophy. In: Proceedings of the National Academy of Sciences of the United States of America. 2016 ; Vol. 113, No. 34. pp. 9593-9598.
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abstract = "Multiple system atrophy (MSA) is a sporadic orphan neurodegenerative disorder. No treatment is currently available to slow down the aggressive neurodegenerative process, and patients die within a few years after disease onset. The cytopathological hallmark of MSA is the accumulation of alpha-synuclein (α-syn) aggregates in affected oligodendrocytes. Several studies point to α-syn oligomerization and aggregation as a mediator of neurotoxicity in synucleinopathies including MSA. C-terminal truncation by the inflammatory protease caspase-1 has recently been implicated in the mechanisms that promote aggregation of α-syn in vitro and in neuronal cell models of α-syn toxicity. We present here an in vivo proof of concept of the ability of the caspase-1 inhibitor prodrug VX-765 to mitigate α-syn pathology and to mediate neuroprotection in proteolipid protein α-syn (PLP-SYN) mice, a transgenic mouse model of MSA. PLP-SYN and age-matched wild-type mice were treated for a period of 11 wk with VX-765 or placebo. VX-765 prevented motor deficits in PLP-SYN mice compared with placebo controls. More importantly, VX-765 was able to limit the progressive toxicity of α-syn aggregation by reducing its load in the striatum of PLP-SYN mice. Not only did VX-765 reduce truncated α-syn, but it also decreased its monomeric and oligomeric forms. Finally, VX-765 showed neuroprotective effects by preserving tyrosine hydroxylase-positive neurons in the substantia nigra of PLP-SYN mice. In conclusion, our results suggest that VX-765, a drug that was well tolerated in a 6 wk-long phase II trial in patients with epilepsy, is a promising candidate to achieve disease modification in synucleinopathies by limiting α-syn accumulation.",
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AU - Leste-Lasserre, Thierry

AU - Hoang, Quyen

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AU - Meissner, Wassilios G.

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