Imagine a bustling city with an intricate transportation system, keeping everything running smoothly. Now, picture this system starting to break down, causing traffic jams and delays throughout the city. In a similar way, mutations in the glucocerebrosidase (GBA) gene can disrupt the delicate balance of mitochondria and lysosomes in Parkinson’s disease (PD). GBA mutations, the most important genetic risk factors for PD, can lead to dysfunction in these cellular compartments, potentially contributing to the development of PD. Researchers are still unraveling the exact mechanisms behind this connection, but evidence points to issues with mitochondrial function, impaired recycling systems within cells (autophagy-lysosomal dysfunction), disrupted lipid regulation, and the accumulation of a protein called α-synuclein. These findings not only enhance our understanding of PD but also offer potential therapeutic targets. Approaches like enzyme replacement, reducing harmful substrates, gene therapy, and small molecules that promote proper protein folding are being explored as strategies to slow down PD progression in individuals with GBA mutations. By delving deeper into the intricate workings of these cellular processes, we can uncover new avenues for treating and managing PD.

Parkinson’s disease (PD) is the second most common neurodegenerative disease and is characterized by multiple motor and non-motor symptoms. Mutations in the glucocerebrosidase (GBA) gene, which encodes the lysosomal enzyme glucocerebrosidase (GCase), which hydrolyzes glucosylceramide (GlcCer) to glucose and ceramide, are the most important and common genetic PD risk factors discovered to date. Homozygous GBA mutations result in the most common lysosomal storage disorder, Gaucher’s disease (GD), which is classified according to the presence (neuronopathic types, type 2 and 3 GD) or absence (non-neuronopathic type, type 1 GD) of neurological symptoms. The clinical manifestations of PD in patients with GBA mutations are indistinguishable from those of sporadic PD at the individual level. However, accumulating data have indicated that GBA-associated PD patients exhibit a younger age of onset and a greater risk for cognitive impairment and psychiatric symptoms. The mechanisms underlying the increased risk of developing PD in GBA mutant carriers are currently unclear. Contributors to GBA-PD pathogenesis may include mitochondrial dysfunction, autophagy-lysosomal dysfunction, altered lipid homeostasis and enhanced α-synuclein aggregation. Therapeutic strategies for PD and GD targeting mutant GCase mainly include enzyme replacement, substrate reduction, gene and pharmacological small-molecule chaperones. Emerging clinical, genetic and pathogenic studies on GBA mutations and PD are making significant contributions to our understanding of PD-associated pathogenetic pathways, and further elucidating the interactions between GCase activity and neurodegeneration may improve therapeutic approaches for slowing PD progression.

Read Full Article (External Site)