Pathological Mechanisms and Clinical Aspects of GBA1 Mutation-Associated Parkinson’s Disease

ABSTRACT

Parkinson’s disease (PD) is a common neurodegenerative disorder, characterized by a motor syndrome consisting of bradykinesia, rigidity, resting tremor, and postural instability. Mutation in the GBA1 gene, which encodes the lysosomal enzyme glucocerebrosidase, has recently emerged as the most com­mon genetic abnormality associated with PD. Approximately 5% of PD patients carry a GBA1 mutation, in comparison to <1% of the healthy population. Heterozygous or homozygous GBA1 mutations increase the risk of PD 20–30 fold. The pathogenic mechanisms of GBA1 mutation-associated PD are not fully understood. Several studies suggest loss of enzyme activity underlies the patho­genicity of GBA1 mutations, while others suggest that a gain of function due to enzyme misfolding is important. Lysosomal-autophagic and mitochondrial dysfunction, as well as endoplasmic reticulum stress and alpha-synuclein accu­mulation, have all been demonstrated in association with GBA1 mutation. The clinical features of GBA1 mutation-associated PD are similar to that of sporadic disease but with an earlier age of onset and a more rapid cognitive and motor decline. Given this impact of clinical course and its relatively high frequency, understanding the pathogenic mechanisms of GBA1 mutations will allow for the development of targeted, potentially disease-modifying treatments that will have implications for many patients with PD.