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

Abstract

<i>Glucosylceramidase beta 1</i> (<i>GBA1</i>) 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 <i>GBA1</i> 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 <i>GBA1</i>-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 <i>GBA1</i>-regulated pathway by repositioning treatment strategies for Gaucher’s disease. This review summarizes the current hypotheses on a mechanistic link between <i>GBA1</i> variants and PD and possible therapeutic options for modulating <i>GBA1</i>-regulated pathways in PD patients.