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

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 ac...

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Autores principales: Viel, Catherine, Clarke, Jennifer, Kayatekin, Can, Richards, Amy M., Chiang, Ming Sum R., Park, Hyejung, Wang, Bing, Shihabuddin, Lamya S., Sardi, S. Pablo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8536659/
https://www.ncbi.nlm.nih.gov/pubmed/34686711
http://dx.doi.org/10.1038/s41598-021-00404-5
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author Viel, Catherine
Clarke, Jennifer
Kayatekin, Can
Richards, Amy M.
Chiang, Ming Sum R.
Park, Hyejung
Wang, Bing
Shihabuddin, Lamya S.
Sardi, S. Pablo
author_facet Viel, Catherine
Clarke, Jennifer
Kayatekin, Can
Richards, Amy M.
Chiang, Ming Sum R.
Park, Hyejung
Wang, Bing
Shihabuddin, Lamya S.
Sardi, S. Pablo
author_sort Viel, Catherine
collection PubMed
description 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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spelling pubmed-85366592021-10-25 Preclinical pharmacology of glucosylceramide synthase inhibitor venglustat in a GBA-related synucleinopathy model Viel, Catherine Clarke, Jennifer Kayatekin, Can Richards, Amy M. Chiang, Ming Sum R. Park, Hyejung Wang, Bing Shihabuddin, Lamya S. Sardi, S. Pablo Sci Rep Article 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. Nature Publishing Group UK 2021-10-22 /pmc/articles/PMC8536659/ /pubmed/34686711 http://dx.doi.org/10.1038/s41598-021-00404-5 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Viel, Catherine
Clarke, Jennifer
Kayatekin, Can
Richards, Amy M.
Chiang, Ming Sum R.
Park, Hyejung
Wang, Bing
Shihabuddin, Lamya S.
Sardi, S. Pablo
Preclinical pharmacology of glucosylceramide synthase inhibitor venglustat in a GBA-related synucleinopathy model
title Preclinical pharmacology of glucosylceramide synthase inhibitor venglustat in a GBA-related synucleinopathy model
title_full Preclinical pharmacology of glucosylceramide synthase inhibitor venglustat in a GBA-related synucleinopathy model
title_fullStr Preclinical pharmacology of glucosylceramide synthase inhibitor venglustat in a GBA-related synucleinopathy model
title_full_unstemmed Preclinical pharmacology of glucosylceramide synthase inhibitor venglustat in a GBA-related synucleinopathy model
title_short Preclinical pharmacology of glucosylceramide synthase inhibitor venglustat in a GBA-related synucleinopathy model
title_sort preclinical pharmacology of glucosylceramide synthase inhibitor venglustat in a gba-related synucleinopathy model
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8536659/
https://www.ncbi.nlm.nih.gov/pubmed/34686711
http://dx.doi.org/10.1038/s41598-021-00404-5
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