GBA1/glucocerebrosidase

Class

enzyme chaperone (repurposed)

Glucocerebrosidase (GCase) is a lysosomal enzyme encoded by the GBA1 gene that breaks down a lipid called glucosylceramide into simpler components. When GCase activity is reduced, this lipid and a related metabolite accumulate inside lysosomes, impairing the cell's capacity to clear waste products. Complete loss of GCase activity causes Gaucher disease, a rare inherited disorder affecting the spleen, liver, bone, and sometimes the brain. Partial reductions, including those seen in carriers of a single mutated GBA1 copy, are the most common known genetic risk factor for Parkinson's disease, where lysosomal dysfunction is thought to promote the accumulation of misfolded alpha-synuclein protein in neurons. Because of this, restoring or boosting GCase activity is pursued as a strategy for both conditions, though with different practical challenges: Gaucher disease affects peripheral organs, while Parkinson's disease requires the therapy to reach the brain. Two broad approaches appear here: small-molecule chaperones that help misfolded GCase protein fold correctly and reach the lysosome, and gene therapies that deliver a functional copy of GBA1 to increase enzyme production directly in target tissue, including the central nervous system. Both aim to increase functional GCase levels, but by different means and with different durability and delivery trade-offs.