Significance Multiple system atrophy (MSA) is a fatal neurodegenerative disorder associated with the accumulation of alpha-synuclein (α-syn) aggregates in oligodendrocytes. There is currently no treatment to slow down the aggressive neurodegenerative process. C-terminal truncation of α-syn promotes the formation of oligomers and aggregates that, in turn, mediate neurotoxicity in synucleinopathies including MSA. We present here an in vivo proof of concept of the ability of the caspase-1 inhibitor VX-765 to mitigate α-syn pathology and provide neuroprotection in a transgenic mouse model of MSA through reduction of α-syn C-terminal truncation. These findings suggest that VX-765, a well-tolerated drug in a 6 wk-long phase II trial in patients with epilepsy, is a promising candidate to achieve disease modification in MSA by limiting α-syn accumulation.