Role of Lipid Dyshomeostasis in Cognitive Dysfunction of Parkinson s Disease
Abstract
Rationale: The brain is composed of lipids that play a crucial role in maintaining structure and function. Recent studies on human brains donated at death noted abnormal lipid accumulation in the nervous tissue of patients with neurodegenerative disorders. Parkinson s disease (PD) is one such debilitating neurodegenerative disorder that primarily affects the elderly. A recent survey of PD patients and their caregivers identifies preservation of cognitive functions including memory and learning abilities as a major unmet need. In this proposal, we will test whether brain lipid accumulation contributes to cognitive dysfunction in PD, through the study of PD that arises due to mutations in the gene GBA. The GBA mutation is the biggest risk for PD and leads to disease with severe cognitive symptoms, including deficits in memory, learning, and problem solving. GBA encodes an enzyme called glucocerebrosidase 1 (Gcase1), which plays a prominent role in breaking down a special class of lipids called glycosphingolipids (GSLs), mainly glucosylceramide (GlcCer) and glucosylsphingosine (GlcSph). Discovery from our lab published in The Journal of Neuroscience showed that accumulation of these GSLs in the brains of mouse models lacking GBA leads to subsequent aggregation of the protein "alpha-synuclein," which characterizes PD. In the current proposal, we hypothesize that a similar accumulation of GSLs and subsequent cellular disturbances in the hippocampus and cortex drive cognitive decline in PD. Objectives and Aims of the Project: The hippocampus and cortex are the main brain structures that control cognition. Therefore, we will perform detailed evaluation of the hippocampus and cortex in our established mouse model of GBA-associated PD. Through a method called lipidomics, we will identify what type(s) of lipids or GSLs accumulate in the hippocampus and cortex throughout PD progression. We will further conduct experiments to test learning and memory in these mice, as well as examine how accumulation of GSLs affect cells in the hippocampus and cortex. Finally, we will evaluate how abnormal lipid accumulation affects synaptic health, electrical activity, and function in the hippocampus. With a goal of identifying therapeutic targets, we will test if blocking GSL accumulation in the hippocampus of our GBA-associated PD models can protect the mice from developing PD-associated learning and memory deficits. These studies will form the basis of novel treatment and preventive strategies that mitigate cognitive dysfunction in PD. Applicability: PD is diagnosed by measuring motor abnormalities. Within several years of diagnosis, 80% of patients develop cognitive problems. While this statistic provides a window for preventive measures against cognitive decline, current understanding of the mechanisms through which cognitive problems arise is severely lacking. Our proposed research aims to provide a breakthrough in this field by identifying lipids as important modifiers of cognitive dysfunction in PD. GSL accumulation in bodily fluids like blood could be used in the future as a diagnostic tool for PD and as an indicator of risk for cognitive decline. Similar GBA dysfunction is also known to cause dementia with Lewy bodies (DLB), which is closely related to PD. Gcase1 deficiency and GSLs accumulation are observed in the brains of PD patients even without GBA mutations. Therefore, our study is of broader relevance to all PD patients, along with other cognitive disorders like DLB. Several commercially available drugs actually block accumulation of GSLs such as GlcSph in cancer. Drugs targeting GlcCer are under clinical trials for Gaucher disease, where GBA mutation is the primary cause. Confirmation of the role of GSLs in cognitive dysfunction of PD, would suggest that these existing drugs could be repurposed for PD and potentially treat patients within 5-10 years from completion of this project. In summary, our proposal aligns with the interest
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jul 16, 2019
- Source ID
- W81XWH1910264
Entities
People
- D J Vidyadhara
Organizations
- United States Army
- Yale University