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NIH grant 1R01NS150750-01: Investigating the toxicity of Lipid-rich-alpha-synuclein inclusions
Institute: {'code': 'NS', 'abbreviation': 'NINDS', 'name': 'National Institute of Neurological Disorders and Stroke', 'admin_org_id': '12500053', 'admin_funding_url': ''}. PI: Eleanna Kara. Award: $617246.
Start: 2026-09-26T00:00:00.
PROJECT SUMMARY
Lewy bodies are the defining pathology of Parkinson’s disease (PD). Although traditionally viewed as fibrillar
alpha-synuclein (αSyn) aggregates, recent studies on postmortem brain tissue, particularly in the substantia
nigra, showed that a substantial fraction of Lewy bodies are enriched in vesicles, membranes, and lipids coated
by amorphously aggregated αSyn. Additional types of lipid-rich αSyn inclusions are prevalent in brainstem
regions and particularly in the substantia nigra, such as pale bodies and lipid-laden neuritic inclusions. This
suggests that lipid-rich αSyn pathology may be especially frequent in the substantia nigra and contribute to its
early degeneration. Nigral dopaminergic neurons contain abundant neuromelanin with associated lipid droplets,
a feature linked to oxidative stress. Convergent evidence indicates bidirectional αSyn-lipid droplet dysregulation:
αSyn overexpression drives lipid droplet accumulation; αSyn binding to lipid droplets yields proteolysis-resistant
αSyn species and suppresses triglyceride turnover. We hypothesize that the lipid droplet-rich milieu of brainstem
dopaminergic neurons nucleates aberrant liquid-liquid phase separation of αSyn, producing frequent lipid
droplet-rich condensates that are selectively toxic to mitochondria; given the high energy demands of
dopaminergic neurons, this promotes early energy failure and neurodegeneration. Understanding the
mechanisms linking lipid droplets, αSyn condensates, and mitochondrial dysfunction to the selective
degeneration of the substantia nigra can help nominate druggable targets to prevent or reverse lipid-rich αSyn
toxicity in PD.document fetched 2026-10-04 02:43