SEARCHNARRATIVE_REVIEWneurology, biomedical research

narrative_review·neurology, biomedical research, preclinical research, systematic review·PMC10548077

GBA1 Variants and Parkinson’s Disease: Paving the Way for Targeted Therapy

Journal of Movement Disorders · 5 authors, 5 centres

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TL;DR

The review covers genotype-phenotype correlations, mechanistic insights, and therapeutic strategies including lessons from the failed MOVES-PD trial.

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GBA1 encodes the lysosomal enzyme β-glucocerebrosidase, and more than 300 variants have been associated with Gaucher's disease. The authors discuss the GBA1-regulated pathway, including dysregulated sphingolipid metabolism, impaired protein quality control, and disrupted ER-Golgi trafficking, as providing new perspectives on PD pathogenesis. A substantial correlation between GBA1 genotypes and PD phenotypes could inform prediction of disease progression, with more aggressive phenotypes observed in patients carrying severe variants. The review highlights the recent failure of the MOVES-PD trial as an important lesson.

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narrative_review

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neurology

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100% · A

ORIGINAL PAPER

PMC10548077

GBA1 Variants and Parkinson’s Disease: Paving the Way for Targeted Therapy

Journal of Movement Disorders

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ABSTRACT

Glucosylceramidase beta 1 ( GBA1 ) variants have attracted enormous attention as the most promising and important genetic candidates for precision medicine in Parkinson’s disease (PD). A substantial correlation between GBA1 genotypes and PD phenotypes could inform the prediction of disease progression and promote the development of a preventive intervention for individuals at a higher risk of a worse disease prognosis. Moreover, the GBA1 -regulated pathway provides new perspectives on the pathogenesis of PD, such as dysregulated sphingolipid metabolism, impaired protein quality control, and disrupted endoplasmic reticulum-Golgi trafficking. These perspectives have led to the development of novel disease-modifying therapies for PD targeting the GBA1 -regulated pathway by repositioning treatment strategies for Gaucher’s disease. This review summarizes the current hypotheses on a mechanistic link between GBA1 variants and PD and possible therapeutic options for modulating GBA1 -regulated pathways in PD patients.

CITATION EXPORT

Young Eun Huh, Tatiana Usnich, Clemens R. Scherzer et al.. GBA1 Variants and Parkinson’s Disease: Paving the Way for Targeted Therapy. Journal of Movement Disorders. (2023). https://doi.org/10.14802/jmd.23023

AUTHORS

5 · 5 CENTRES

Young Eun Huh, Tatiana Usnich, Clemens R. Scherzer, Christine Klein, Sun Ju Chung

1Department of Neurology, CHA Bundang Medical Center, CHA University, Seongnam, Korea
2Institute of Neurogenetics, University of Lübeck and University Hospital of Schleswig-Holstein, Lübeck, Germany
3Advanced Center for Parkinson’s Disease Research, Harvard Medical School, Brigham and Women’s Hospital, Boston, MA, USA
4Precision Neurology Program, Harvard Medical School, Brigham and Women’s Hospital, Boston, MA, USA
5Department of Neurology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea