Although the exact mechanism by which GBA1 mutations promote PD is unknown, current understanding suggests that impaired GCase inhibits lysosomal activity and decreases the overall ability of the cell to degrade proteins, specifically the neuronal protein α-synuclein.
We performed a genome-wide association study and analysed the most recent Parkinson's disease-associated genetic risk score to detect genetic influences on GBA risk and age at onset.
Screening of the GBA1 gene and analysis of CSF levels of total alpha-synuclein were performed in 80 PD<sub>GBA</sub> , 80 PD<sub>GBA</sub> _<sub>wildtype</sub> and 39 healthy controls cross-sectionally.
In preparation for upcoming precision medicine-designed clinical trials for GBA and LRRK2, we evaluated movement disorders specialists' current practice, knowledge, attitudes, and barriers to genetic testing in PD.
We aimed to examine whether non-manifesting carriers of LRRK2 and GBA mutations have prodromal features of Parkinson's disease that correlate with reduced DAT binding.
The finding that mutations in the Gaucher's Disease (GD) gene GBA1 are a strong risk factor for Parkinson's Disease (PD) has allowed for unique insights into pathophysiology centered on disruption of the autophagic-lysosomal pathway.
Despite the evidence of multiple lysosomal genetic risks, it remains unclear how sphingolipid hydrolase activities, other than GBA, are altered with ageing or in PD.
We confirmed the gross deletion mutation in the GBA gene, which appeared to be associated with the PD or reduced [<sup>123</sup>I] FP-CIT in this family.
With regard to GBA-PD, iPSCs offer several advantages including the possibility of investigating sphingolipid (SPL) biology in relevant cells, the role of dopamine metabolism as well as non-cell autonomous mechanisms that are likely involved in the disease process.
Using high-resolution, single-cell transcriptomic analyses of iPSC-derived dopamine neurons carrying the GBA-N370SPD risk variant, we identified a progressive axis of gene expression variation leading to endoplasmic reticulum stress.
GBA1 heterozygous mutations profoundly impair GCase activity and are currently recognized as an important risk factor for the development of Parkinson's disease (PD).
Our findings point to activation of wild-type GCase by small-molecule modulators as a potential therapeutic approach for treating familial and sporadic forms of PD that exhibit decreased GCase activity.
Epidemiological studies helped promote research in the field that continues to improve our understanding of the link between mutations in the glucocerebrosidase (GBA) gene and PD.
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.
Heterozygous mutations of the lysosomal enzyme glucocerebrosidase (GBA1) represent the major genetic risk for Parkinson's disease (PD), while homozygous GBA1 mutations cause Gaucher disease, a lysosomal storage disorder, which may involve severe neurodegeneration.