Since the observation of its relation to PD, GBA1 mutations have become recognized as the most common genetic risk factor for development of synucleinopathies such as PD and dementia with Lewy bodies.
Mutations in the gene glucocerebrosidase (GBA1) are specifically associated with alpha-synucleinopathies, namely, Parkinson's disease (PD) and dementia with Lewy bodies.
Variants in the ASH1L/GBA (Chr1q22) and APOE ε4 (Chr19) loci were associated with DLB surpassing the genome-wide significance threshold (p < 5 × 10<sup>-8</sup>).
Mutations in the GBA1 gene, which encodes the lysosomal enzyme Glucocerebrosidase1 are major risk factors for Parkinson's disease (PD) and dementia with Lewy bodies (DLB).
The characterization of a direct link between mutations in the gene coding for glucocerebrosidase (GBA1) with the development of Parkinson's disease and dementia with Lewy bodies has heightened interest in this enzyme.
Mutations in GBA1, the gene encoding the lysosomal hydrolase glucocerebrosidase, have been identified as the most common genetic risk factor for PD and DLB.
Gaucher's disease is a lysosomal disease caused by mutations in the β-glucocerebrosidase gene ( GBA1 and GCase) that have been also linked to increased risk of Parkinson's disease (PD) and Diffuse Lewy body dementia.
GBA1 mutations, which result in the lysosomal disorder Gaucher disease, are the most common known genetic risk factor for Parkinson disease and Dementia with Lewy Bodies (DLB).
For example, research has expanded our knowledge of the proteinaceous inclusions that characterize the disease, has provided an appreciation of the role of disease-associated processes such as inflammation and has revealed an association between DLB and genes such as GBA.
We also briefly summarize the development of targeted therapies for GBA1-associated synucleinopathies and highlight that modulation of wild-type GCase activity serves as an important target for the treatment of genetic and idiopathic forms of PD and dementia with Lewy bodies.
The reduction of GCase activity in the CSF of PD and DLB patients was validated in several of them, whereas the behaviour of other lysosomal enzyme activities was not consistently reliable among the studies.
The L444P mutation in the GBA1 gene which encodes β-glucocerebrosidase-1, is a major risk factor for developing Parkinson's disease (PD) and dementia with Lewy bodies (DLB).
We thus propose that acid ceramidase inhibition which restores ceramide levels may be a potential therapeutic strategy to target synucleinopathies linked to GBA1 mutations including PD and DLB.
GBA1 mutations reduce GCase activity, therefore promoting the aggregation of alpha-synuclein, a common neuropathological finding underlying Parkinson's disease (PD) and dementia with Lewy bodies.
Furthermore, genetic and clinicopathological studies have revealed mutations in the glucocerebrosidase 1 (GBA1) gene, which encodes a degrading enzyme for the glycolipid glucosylceramide (GlcCer), as strong risk factors for PD and DLB, and we recently demonstrated that GlcCer promotes toxic conversion of αSyn.
Glucocerebrosidase (GBA) gene variants are associated with the development of the Lewy body disorders (LBD) Parkinson disease (PD) and dementia with Lewy bodies (DLB).
Taken together, these studies provide mechanistic insights into how GBA1 regulates the transition from monomeric α-syn to α-syn tetramers and multimers and suggest unique therapeutic opportunities for PD and dementia with Lewy bodies.
Mutations in the glucocerebrosidase (GBA) gene are a strong genetic risk factor for the development of Parkinson's disease and dementia with Lewy Bodies.
More recently, association and exome sequencing studies in larger groups have been conducted, and have shown that several variants in GBA and the APOE ε4 allele are important genetic risk factors for DLB.