Double-Edged Effects of Venglustat on Behavior and Pathology in Mice Overexpressing alpha-Synuclein

Background: Venglustat is a brain-penetrant, small molecule inhibitor of glucosylceramide synthase used in clinical testing for treatment of Parkinson's disease (PD). Despite beneficial effects in certain cellular and rodent models, patients with PD with mutations in GBA, the gene for lysosomal glucocerebrosidase, experienced worsening of their motor function under venglustat treatment (NCT02906020, MOVES-PD, phase 2 trial). Objective: The objective of this study was to evaluate venglustat in mouse models of PD with overexpression of wild-type alpha-synuclein. Methods: Mice overexpressing alpha-synuclein (Thy1-aSyn line 61) or Gba-mutated mice with viral vector-induced overexpression of alpha-synuclein in the substantia nigra were administered venglustat as food admixture. Motor and cognitive performance, alpha-synuclein-related pathology, and microgliosis were compared with untreated controls. Results: Venglustat worsened motor function in Thy1-aSyn transgenics on the challenging beam and the pole test. Although venglustat did not alter the cognitive deficit in the Y-maze test, it alleviated anxiety-related behavior in the novel object recognition test. Venglustat reduced soluble and membrane-bound alpha-synuclein in the striatum and phosphorylated alpha-synuclein in limbic brain regions. Although venglustat reversed the loss of parvalbumin immunoreactivity in the basolateral amygdala, it tended to increase microgliosis and phosphorylated alpha-synuclein in the substantia nigra. Furthermore, venglustat also partially worsened motor performance and tended to increase neurofilament light chain in the cerebrospinal fluid in the Gba-deficient model with nigral alpha-synuclein overexpression and neurodegeneration. Conclusions: Venglustat treatment in two mouse models of alpha-synuclein overexpression showed that glucosylceramide synthase inhibition had differential detrimental or beneficial effects on behavior and neuropathology possibly related to brain region-specific effects. (c) 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.