Glucosylceramide synthase inhibition alleviates aberrations in synucleinopathy models

Abstract

Mutations in the glucocerebrosidase gene (<i>GBA</i>) confer a heightened risk of developing Parkinson's disease (PD) and other synucleinopathies, resulting in a lower age of onset and exacerbating disease progression. However, the precise mechanisms by which mutations in <i>GBA</i> increase PD risk and accelerate its progression remain unclear. Here, we investigated the merits of glucosylceramide synthase (GCS) inhibition as a potential treatment for synucleinopathies. Two murine models of synucleinopathy (a Gaucher-related synucleinopathy model, <i>Gba</i>^{<i>D409V/D409V</i>} and a A53T-α-synuclein overexpressing model harboring wild-type alleles of <i>GBA</i>, <i>A53T-SNCA</i> mouse model) were exposed to a brain-penetrant GCS inhibitor, GZ667161. Treatment of <i>Gba</i>^{<i>D409V/D409V</i>} mice with the GCS inhibitor reduced levels of glucosylceramide and glucosylsphingosine in the central nervous system (CNS), demonstrating target engagement. Remarkably, treatment with GZ667161 slowed the accumulation of hippocampal aggregates of α-synuclein, ubiquitin, and tau, and improved the associated memory deficits. Similarly, prolonged treatment of <i>A53T-SNCA</i> mice with GZ667161 reduced membrane-associated α-synuclein in the CNS and ameliorated cognitive deficits. The data support the contention that prolonged antagonism of GCS in the CNS can affect α-synuclein processing and improve behavioral outcomes. Hence, inhibition of GCS represents a disease-modifying therapeutic strategy for <i>GBA</i>-related synucleinopathies and conceivably for certain forms of sporadic disease.