OBESITY AND AGING AS RISK FACTORS FOR LIPID DROPLET ACCUMULATION AND Α-SYNUCLEIN PATHOLOGY IN PARKINSON’S DISEASE

Lipid metabolism is essential for the development and function of neurons and glia in the brain. It governs various functions, including the maintenance of structural integrity, myelination, energy homeostasis, and immune regulation in the central nervous system (CNS). Disruption to these processes can lead to altered lipid levels and an increased number of intracellular lipid droplets (LDs) in dopaminergic and glial cells, resulting in α-synuclein aggregation-mediated neuroinflammation and neurodegenerative diseases, such as Parkinson's disease (PD). Obesity and aging significantly impact systemic and brain lipid homeostasis, potentially leading to lipid disturbances, such as elevated triacylglyceride (TAG), diacylglyceride (DAG), and LD levels. However, the mechanisms connecting peripheral lipid dysregulation to CNS pathology are unclear.
We hypothesize that a high-fat diet enhances the age-dependent increase of TAGs and DAGs, as well as their translocation to the CNS. There, they increase LD levels in glia and exacerbate PD pathology via α-synuclein-linked neurodegeneration. Mice receive fibril injections at 40 weeks of age, followed by a dietary intervention (standard versus high-fat diet) and analysis at 60 weeks. Blood, cerebrospinal fluid, adipose tissue, and Parkinson’s disease–relevant brain regions (striatum, substantia nigra, and cortex) will be collected for lipidomic analysis. Lipid droplet (LD) abundance in glial cells will be quantified, and dysregulated pathways related to lipid metabolism, inflammation, and α-synuclein pathology will be analyzed.
These analyses will help us understand how aging and obesity interact to alter peripheral and central lipid metabolism and further help us identify biomarkers associated with LD accumulation and PD pathology.