Role of Lipid Dyshomeostasis in Cognitive Dysfunction of Parkinson's Disease
Abstract
Cognitive decline is a major non-motor dysfunction of Parkinson's disease (PD), still, little is known regarding the cellular mechanisms. Cognitive dysfunction is predominant in PD patients with GBA mutations who primarily develop Gaucher disease (GD). GBA is also the most common risk gene for Dementia with Lewy Bodies (DLB), a leading cause of dementia and cognitive disabilities. DLB shares synuclein aggregation pathology with that of PD. In this study, we used novel Gba mutant mice that develop GD to unravel the pathogenic mechanisms for cognitive decline in PD and DLB. We also generated double transgenic mice by crossing Gba mutants with SNCA transgenic mice model of PD to evaluate how-synuclein aggregation might alter Gba/Gcase1 deficiency-mediated pathology and vice versa. Gba mutants did not show age-related PD-like motor deficits which were apparent in SNCA transgenic mice. However, Gba mutation in SNCA transgenic mice exacerbated the motor deficits. Gba mutants showed cognitive deficits, which, interestingly did not worsen with age. Gba-SNCA double transgenics showed similar cognitive deficits, whereas SNCA transgenics were cognitively normal. These results suggest that Gba/Gcase1 deficiency can independently impart cognitive decline, and when it co-occur with alpha-synuclein pathology as seen in Gba-SNCA double transgenics, it exacerbates the motor dysfunction. In the cognitive brain areas such as cortex and hippocampus, Gba mutants did not show pathological alpha-synuclein aggregation, however, an exacerbated alpha-synuclein pathology was seen in Gba-SNCA double transgenics. Unbiased proteomics of brains from these mice suggested a dysfunctional lipid metabolism in Gba mutants, which when co-existed with alpha-synuclein pathology as seen in double transgenics, leads to dysregulation in sirtuin signalling and reactive oxygen species production pathways.
Document Details
- Document Type
- Technical Report
- Publication Date
- Nov 01, 2022
- Accession Number
- AD1191538
Entities
People
- D J Vidyadhara
Organizations
- Yale University