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

AI Article Synopsis

  • Mutations in the GBA gene, linked to the enzyme glucocerebrosidase, significantly increase the risk of developing Parkinson's disease and can lead to earlier and faster progression of symptoms in affected patients.
  • Research using mouse models indicates that targeting the sphingolipid metabolism pathway through inhibition of glucosylceramide synthase (GCS) could be a viable treatment for synucleinopathies.
  • A clinical candidate GCS inhibitor, venglustat, was tested and showed promising results in reducing harmful lipid accumulation and improving cognitive function in models that simulate GBA-linked Parkinson's disease.

Article Abstract

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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8536659PMC
http://dx.doi.org/10.1038/s41598-021-00404-5DOI Listing

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