Journal Article

Preclinical pharmacology of glucosylceramide synthase inhibitor venglustat in a GBA-related synucleinopathy model

Shihabuddin, Lamya S., Chiang, Ming Sum R., Clarke, Jennifer, Kayatekin, Can, Wang, Bing, Sardi, S. Pablo, Park, Hyejung, Viel, Catherine, Richards, Amy M.

2021

Overview

Mutations in GBA , the gene encoding the lysosomal enzyme glucocerebrosidase (GCase), represent the greatest genetic risk factor for developing synucleinopathies including Parkinson’s disease (PD). Additionally, PD patients harboring a mutant GBA allele present with an earlier disease onset and an accelerated disease progression of both motor and non-motor symptoms. Preclinical studies in mouse models of synucleinopathy suggest that modulation of the sphingolipid metabolism pathway via inhibition of glucosylceramide synthase (GCS) using a CNS-penetrant small molecule may be a potential treatment for synucleinopathies. Here, we aim to alleviate the lipid storage burden by inhibiting the de novo synthesis of the primary glycosphingolipid substrate of GCase, glucosylceramide (GlcCer). We have previously shown that systemic GCS inhibition reduced GlcCer and glucosylsphingosine (GlcSph) accumulation, slowed α-synuclein buildup in the hippocampus, and improved cognitive deficits. Here, we studied the efficacy of a brain-penetrant clinical candidate GCS inhibitor, venglustat, in mouse models of GBA -related synucleinopathy, including a heterozygous Gba mouse model which more closely replicates the typical GBA -PD patient genotype. Collectively, these data support the rationale for modulation of GCase-related sphingolipid metabolism as a therapeutic strategy for treating GBA- related synucleinopathies.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 631/154 / 631/154/436 / 631/378 / 631/378/1689 / Animal models / Animals / Carbamates - pharmacology / Ceramide glucosyltransferase / Cognitive ability / Disease Models, Animal / Genotypes / Glucosylceramidase / Glucosylceramidase - metabolism / Glucosylceramides - metabolism / Glucosyltransferases - antagonists & inhibitors / Hippocampus - drug effects / Hippocampus - metabolism / Humanities and Social Sciences / Lipid metabolism / Metabolism / Mice / Mice, Inbred C57BL / Movement disorders / multidisciplinary / Mutation - genetics / Neurodegenerative diseases / Parkinson Disease - metabolism / Parkinson's disease / Patients / Pharmacology / Quinuclidines - pharmacology / Risk factors / Science / Science (multidisciplinary) / Synuclein / Synucleinopathies - drug therapy / Synucleinopathies - metabolism