| dc.description.abstract | Parkinson disease (PD) is a common neurodegenerative disease and associated with pronounced loss of dopaminergic (DA) neurons in a region of the brain. The disease has been found to be caused by a combination of genetic variations, environmental factors and aging. Many of the PD-related genetic variations are identified in genes involved in common biological pathways with critical cellular functions. Mutations in the GBA1 gene are a well- known risk factor in PD, and recently genetic variation in scavenger receptor class B member 2 (SCARB2) has been associated with PD risk. GBA1 and SCARB2 encode glucocerebrosidase (GCase) and lysosomal integral membrane protein-2 (LIMP-2), respectively. These are part of the same lysosomal pathway in which trafficking of GCase from the endoplasmic reticulum (ER) to the lysosome is mediated by LIMP-2. Interestingly, impaired GCase function has been associated with PD, however the mechanism of LIMP-2 is unknown.
The aim of our project was to investigate the possible role of SCARB2/LIMP-2 in the pathogenesis of PD and the connection to GBA1-PD and GCase activity. To achieve this, two approaches were taken. Firstly, by assessing the rs6812193 polymorphism, located upstream of SCARB2, and its association with PD of risk and progression. For the genetic analysis, 470 PD patients and 419 control subjects from three different Northern European cohorts were analyzed using TaqMan® Genotyping Assay. Secondly, the LIMP-2 level were analyzed in CSF in 121 PD patients from a Norwegian cohort using Proximity extension assay (PEA) (Olink AS) and the GCase activity was analyzed in CSF in 120 PD patients from a Norwegian cohort using an inhouse fluorometric assay.
Our results show no association between rs6812193 and PD, however we show for the first LIMP-2 protein levels are associated with increased risk of Parkinson disease dementia (PDD). Similarly, GBA1 mutations are associated with higher incidence of PDD. Lastly, no association of the GCase activity level and SCARB2/LIMP-2 was found.
The association of LIMP-2 and GBA1 with increased risk of PDD supports the connection of LIMP-2 and GBA1/GCase in this study, and highlights the importance of further SCARB2/LIMP-2 research to advance our understanding of the mechanism behind PD. | |