Skip to main content

Table 2 The complex role of GBA in PD pathology

From: Towards physiologically relevant human pluripotent stem cell (hPSC) models of Parkinson’s disease

The GBA gene encodes the lysosomal enzyme glucocerebrosidase (GCase), responsible for the hydrolysis of glucocerebroside to glucose and ceramide [101]. Biallelic mutations in GBA result in GCase deficiency and cause Gaucher disease (GD), an autosomal recessive systemic lysosomal storage disorder with a complex pathogenesis [102, 103]. Heterozygous mutations in GBA, have been found to increase the risk of developing PD by 20–30-fold and are more than 5 times more likely to be found in PD patients compared to controls [104,105,106]. Clinical observations show that GBA-associated PD may have an earlier onset and higher risk of developing non-motor symptoms such as dementia and depression [107, 108].
Although the role of GBA mutations as risk factors for PD is well established, the mechanism underlying GBA-associated PD is still not clear.
Glucocerebrosidase has a complex biology. The majority of GBA mutation carriers do not develop PD, and there is great variability in symptoms and clinical presentations in both GD and PD patients carrying the same mutations, suggesting the existence of modifying factors such as gene co-variants and environmental factors [109,110,111]. Decreased GCase activity is also found in patients with PD without GBA mutations, suggesting a central role of the enzyme in the pathogenesis of PD [112, 113]. Many different GBA mutations have been linked to PD disease including those resulting in null alleles and structural protein alteration that can affect stability or trafficking to the lysosome, as well as changes not related to enzymatic activity [114, 115].