A multi-disciplinary team of researchers from several Swedish institutions evaluated the involvement of mutations in glucocerebrosidase (GBA), in the development of Gaucher disease in relationship to Parkinson’s Disease cases.
Three genetic variants were associated with PD in the study population, suggesting that GBA genetic mutations may be risk factors and play a role in PD development; and that lysosomal dysfunction may be involved in the pathogenic mechanisms underlying the disease.
The research paper, “Strong association between glucocerebrosidase mutations and Parkinson’s disease in Sweden”, was published in Neurobiology of Aging.
Previous genetic studies linked mutations in glucocerebrosidase (GBA), which causes Gaucher disease, to an increased risk for Parkinson’s disease (PD). According to the Parkinson’s Disease Foundation, people with Gaucher disease live with 7-9% risk of getting Parkinson’s.
GBA is an enzyme necessary for the metabolism of glucocerebroside, a type of fatty substance. When GBA function is impaired due to mutations, glucocerebroside accumulates in cells and does not get processed by lysosomes, the cellular structures that break down molecules. Recessive mutations of the GBA gene cause Gaucher disease, a lysosomal storage disease.
In the present study, researchers looked into the possible association of GBA mutations and PD and investigated three GBA variants, E326K, N370S, and L444P, in 1625 Swedish PD patients and 2025 control individuals.
N370S, a rare variant, was found in 10 patients (0.63%) and 2 controls (0.10%), showing a trend for association, whereas severe mutation L444P showed a significant association with PD and was found in 35 patients (2.20%) and 3 control individuals (0.15%).
Carriers of the L444P mutation were also found to have lower age of onset of PD symptoms than noncarriers. L444P mutations were more common in northern Sweden, a part of the country with the higher incidence of the Gaucher disease type III. The researchers also found a significant association of the common variant E326K.
The researchers suggest that such findings support the role of GBA mutations as risk factors for PD and the involvement of lysosomal dysfunction in PD pathogenicity.
Authors concluded that further genetic screening and studies of GBA could bring new insights into the pathophysiology of PD, which in turn may result in earlier diagnosis and design of relevant therapeutic strategies.