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

• DOI: 10.1073/pnas.1609291113
• Publication Date: 2016-08-02T03:24:06Z
• Authors: Fares Bassil; Pierre-Olivier Fe...; Erwan Bezard; Alain Pruvost; Thierry Leste-Las...; Quyen Q. Hoang; Dagmar Ringe; Gregory A. Petsko; Wassilios G. Meis...
• Keywords: Neurotoxicity

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