New evidence on the clinical, genetic, and biochemical bases of GBA1-Parkinson's disease: prospects for treatment.

Abstract

GBA1 variants are common genetic risk factors for Parkinson's disease and also for dementia with Lewy bodies. New evidence highlights the relationship between the different GBA1 variants and their associated clinical presentation and disease progression, although penetrance is low and the majority of carriers do not develop a synucleinopathy. The clinical profile of GBA1-associated Parkinson's disease is characterised by a faster rate of progression with more severe cognitive and autonomic dysfunction than idiopathic Parkinson's disease, particularly in those carrying severe pathogenic variants. The mechanisms involved in phenotypic conversion and disease progression in carriers of GBA1 variants are being elucidated, and this knowledge could be translated into clinically relevant biomarker profiles. GBA1 has become a target for intervention for both GBA1-associated Parkinson's disease and idiopathic Parkinson's disease, with therapeutic strategies aiming to prevent or slow disease progression via pharmacological chaperones, enzymatic allosteric activators, metabolic interventions, and modulation of gene expression.