Objective: To assess the therapeutic efficacy of the caspase-1 inhibitor prodrug VX-765 on alpha-synuclein (α-syn) pathology and neuroprotection in a transgenic mouse model of multiple system atrophy (MSA).

Background: The cytopathological hallmark of MSA is the accumulation of 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 in neuronal cell models of α-syn toxicity.

Methods: Mice were treated via gavage once a day with VX-765 or placebo. At the end of the 11-week treatment period motor coordination and balance were assessed with the traversing beam task. Brains were then extracted and prepared according to the experiments needed. Patches were taken from the motor cortex and striatum of PLP-SYN and WT mice to measure protein levels of high molecular weight and truncated forms of α-syn in addition to IL-1β and Pro-IL-1β levels (to assess caspase-1 activity). 40 μm free-floating coronal sections were collected for histopathological analysis of α-syn inclusions in oligodendrocytes and tyrosine hydroxylase (TH) immunostaining.

Results: VX-765 prevented motor deficits in PLP-SYN mice compared to placebo controls. VX-765 treatment was able to limit the progressive toxicity of α-syn aggregation by reducing its load in the striatum but not in the cortex of PLP-SYN mice. Not only did VX-765 reduce truncated α-syn forms in the striatum but also decreased its monomeric and high molecular weight forms without modifying α-syn mRNA levels. Similar to α-syn levels, VX-765 reduced IL-1β in the striatum but not in the cortex of PLP-SYN mice. Finally, VX-765 showed neuroprotective effects by preserving tyrosine hydroxylase positive neurons in the substantia nigra of PLP-SYN mice.

Conclusions: Our results suggest that VX-765, a drug that was well tolerated in a six-week-long phase 2 trial in patients with epilepsy, is a promising candidate to achieve disease modification in MSA patients by limiting α-syn accumulation.

Part of the data were shown at the 45th Annual Meeting of the Society for Neuroscience, Chicago, USA, Oct17-21, 2015.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/reducing-c-terminal-truncation-mitigates-synucleinopathy-and-neurodegeneration-in-a-transgenic-model-of-multiple-system-atrophy/