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Principal Investigator: Saranna Fanning
Organization: BRIGHAM AND WOMEN'S HOSPITAL
Fiscal Year: 2024
Award: $692,401
Funding agency: National Institute of Neurological Disorders and Stroke
Establishing mechanism-based therapeutics for Parkinson’s disease (PD), Lewy body dementia (LBD) and other
synucleinopathies is a biomedical priority. Neuropathological and genetic discoveries implicate α-synuclein (αS)
in familial and ‘sporadic’ PD. Recent publications identify significant lipid components with misfolded αS in Lewy
bodies and Lewy neurites, transforming how we conceptualize PD pathogenesis, as lipids are central to many
fundamental cellular processes and are highly abundant in the brain. αS has physiologic and pathogenic
interactions with phospholipid membranes and fatty acids (FAs) and alters lipid homeostasis. Here, we propose
in vitro and in vivo approaches to dissect the interplay of αS with lipid membranes. Experiments are focused on
advancing PD-dysregulated LIPE (hormone sensitive lipase) as a candidate therapeutic target for PD/LBD in
vivo and establishing the mechanism of rescue centered on αS:lipid membrane interactions at the synapse. We
posit a dynamic relationship between normal and pathological forms of αS and FAs. Our central hypothesis is
that αS dyshomeostasis results in cellular FA metabolism imbalance, altering αS:membrane interactions and
disease phenotypes. This hypothesis underpins the PI’s central goal in this R01: to return the abnormal disease-
associated cellular lipid/FA content to equilibrium in several compelling cellular and in vivo models of PD and
LBD. This proposal has 2 distinct Aims focused on advancing monounsaturated FA therapeutic strategies,
addressing mechanistic and therapeutic questions. 1. We propose a mechanistic dissection of αS:membrane
interactions at the synapse, investigating disease-associated synaptic vesicle abnormalities, αS aggregation,
and the role of membrane FA composition in disease phenotype rescue. 2. We propose to evaluate LIPE as a
therapeutic target for reversal of motor deficits and αS neuropathology with detailed genetic, biochemical,
and pharmacological analyses in multiple mouse PD/LBD/synucleinopathy models. The PI has already
reported a FA target for PD, SCD inhibition, now in human PD clinical trials. Additionally, the PI has published
data generated in support of this proposal in patient-derived neurons identifying LIPE (a functionally distinct,
innovative target) as a candidate PD/LBD therapeutic target. These 2 distinct but complementary Aims should
advance mechanistic understanding of αS:membrane interactions and progress a candidate therapeutic target
(LIPE) for lipid dysfunction in PD and LBD.
Terms: <3' Untranslated Regions><3'UTR><Acylcholesterol Lipase><Address><Assay><Autoregulation><Behavior><Bilayer Fluidity><Binding><Bioassay><Biochemical><Biochemistry><Biological Assay><Biological Chemistry><Biology><Brain><Brain Nervous System><Brain region><C elegans><C. elegans><C.elegans><Caenorhabditis elegans><Carbamide><Cell Function><Cell Membrane Lipids><Cell Physiology><Cell Process><Cellular Function><Cellular Physiology><Cellular Process><Cholesterol Ester Hydrolase><Cholesterol Esterase><Cholesteryl Oleate Hydrolase><Cholesterylester Hydrolase><Clinical Trials><Corpus Striatum><Corpus striatum structure><Data><Defect><Degradation Pathway><Degradative Pathway><Detergents><Development><Disease><Disorder><Dissection><Drug Targeting><Drugs><Dysfunction><Elaqua XX><Encephalon><Enhancers><Enzyme Gene><Enzymes><Equilibrium><Fatty Acid Metabolism Pathway><Fatty Acids><Fiber><Functional disorder><GWA study><GWAS><Genes><Genetic><Genetic Diseases><Genetic analyses><Goals><Homeostasis><Hormone-Sensitive Lipase><Human><In Vitro><Investigation><LB dementia><Lead><Lewy Bodies><Lewy Body Dementia><Lewy Body Type Senile Dementia><Lewy dementia><Lewy neurites><Lewy-related neurites><Link><Lipase><Lipids><Lipoidal Steroid Esterase><Medical><Medication><Membrane><Membrane Fluidity><Membrane Lipids><Mesencephalon><Mice><Mice Mammals><Mid-brain><Midbrain><Midbrain structure><Modeling><Modern Man><Molecular Interaction><Monounsaturated Fatty Acids><Morphology><Murine><Mus><NAC precursor><NINDS><National Institute of Neurological Diseases and Stroke><National Institute of Neurological Disorders and Stroke><Nerve Cells><Nerve Transmitter Substances><Nerve Unit><Neural Cell><Neurocyte><Neurons><Neurotransmitters><PARK1 protein><PARK4 protein><Paralysis Agitans><Parkinson><Parkinson Disease><Pathogenesis><Pathogenicity><Pathologic><Patients><Pb element><Pharmaceutical Preparations><Phenotype><Phosphatides><Phospholipids><Physiologic><Physiological><Physiological Homeostasis><Physiopathology><Point Mutation><Post-Translational Modification Protein/Amino Acid Biochemistry><Post-Translational Modifications><Post-Translational Protein Modification><Post-Translational Protein Processing><Posttranslational Modifications><Posttranslational Protein Processing><Primary Parkinsonism><Process><Property><Protein Modification><Proteins><Publications><Publishing><Regulation><Reporting><Research><Resistance><Role><SNCA><SNCA protein><Scientific Publication><Stearate Desaturase><Stearoyl-CoA Desaturase><Stearyl-CoA Desaturase><Steroid Hormone Esterase><Sterol Ester Acylhydrolase><Steryl-ester acylhydrolase><Striate Body><Striatum><Subcellular Process><Synapses><Synaptic><Synaptic Vesicles><Synaptosomes><System><Therapeutic><Triacylglycerol Hydrolase><Triacylglycerol Lipase><Triacylglycerol acylhydrolase><Tributyrinase><Triglyceridase><Triglyceride Lipase><Triolean Hydrolase><Unsaturated Fats><Urea><Urea Carbamide><Ureaphil><Vesicle><a-syn><a-synuclein><alpha synuclein><alpha synuclein gene><alphaSP22><asyn><balance><balance function><cholesteryl ester synthase><delta-9 Desaturase><dementia risk><density><developmental><disease phenotype><drug/agent><experiment><experimental research><experimental study><experiments><fat metabolism><fatty acid metabolism><genetic analysis><genetic condition><genetic disorder><genome wide association><genome wide association scan><genome wide association studies><genome wide association study><genomewide association scan><genomewide association studies><genomewide association study><heavy metal Pb><heavy metal lead><in vivo><in vivo Model><infancy><infantile><inhibitor><innovate><innovation><innovative><insight><lipid metabolism><lipidomics><membrane structure><motor deficit><mouse model><murine model><neuronal><neuropathologic><neuropathological><neuropathology><neuroprotection><neuroprotective><non A-beta component of AD amyloid><non A4 component of amyloid precursor><pathophysiology><pharmacologic><promoter><promotor><resistant><response><risk factor for dementia><risk for dementia><social role><sporadic Parkinson's Disease><sterol esterase><striatal><synapse><synaptoneurosome><synucleinopathy><therapeutic agent development><therapeutic candidate><therapeutic development><therapeutic target><tributyrase><triterpenol esterase><unilamellar vesicle><unsaturated dietary fat><unsaturated dietary lipid><unsaturated lipid><whole genome association analysis><whole genome association studies><whole genome association study><α synuclein gene><α-syn><α-synuclein>