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This approach is functionally distinct from, but potentially just as important as, SCD inhibition. Having initially focused on the FA synthetic pathway for synucleinopathy, we have now systematically investigated another major source of cellular FAs, neutral lipid lipase, as a potential therapeutic target. SCD inhibitors have now reached human clinical trials for PD treatment. Collectively, these data strongly suggest an αS/lipid interplay and thereby a potential role for lipids/FA in modulating PD/LBD-relevant αS phenotypes in the brain.Įmerging knowledge of lipid alterations in PD/LBD has recently identified a novel FA-related target, stearoyl-CoA desaturase (SCD), inhibition of which reverses numerous PD-relevant phenotypes in cells 23, 32– 34 and in a PD mouse model 35. Indeed, a systematic GWAS analysis revealed lipids as a common factor among numerous PD-relevant processes, including oxidative stress response, endosomal-lysosomal functioning, ER stress response, and neuronal death 31. Mutations in several genes regulating lipids/FAs are associated with increased risk of PD, and multiple lipid species have been found to be altered in PD patient samples 29, 30. Overexpression of αS promotes LD formation 23– 25, and changes in LD content and distribution have been associated with αS toxicity, neurodegeneration, and membrane trafficking defects 26– 28, indicating that αS expression impacts FA homeostasis 23.

It has physiologic and pathogenic interactions with membrane phospholipids 15– 18 and with FAs 19– 22, and it can alter lipid homeostasis 23. The disease-associated protein αS is a 14 kDa cytosolic polypeptide highly expressed in neurons. Notably, however, LDs are in relatively low abundance in neurons, suggesting that FA synthesis and metabolism maybe even more tightly regulated in the central nervous system to avoid detrimental excess 9, 14. LDs are dynamic organelles present in most pro- and eukaryotic cells 12, 13.

#ONE WAY ANOVA GRAPHPAD PRISM 8 FREE#

One ubiquitous homeostatic mechanism is the storage of FAs as triglycerides (TGs) in cytoplasmic lipid droplets (LDs) that help prevent cytotoxic consequences due to the accumulation of free FAs 10, 11. Cells tightly regulate lipid synthesis, precursor uptake, and subcellular distribution, especially FAs. Lipid and FA homeostasis are essential determinants of neural development, neurotransmission, and receptor activation. The brain is the second most lipid-rich organ in the body 9. Membrane phospholipids are comprised of fatty acyl side chains that differ in carbon chain length and can be saturated or unsaturated, thereby largely determining membrane fluidity and influencing protein–protein and protein–lipid interactions. Lipids contribute fundamentally to many cellular processes, including membrane synthesis, energy storage, signaling, and complex protein modifications. Importantly, a recent publication also identified substantial lipid membrane components in LBs 8. α-Synuclein (αS) has been implicated since 1997 as the major proteinaceous component of LB 6, 7. Lewy bodies (LBs) and Lewy neurites are the neuropathological hallmarks of PD, both in the sporadic (“idiopathic”) and autosomal dominant (familial) forms, and accumulate in Alzheimer’s disease (AD) 1– 5. There is a critical need to develop disease-modifying treatments for human synucleinopathies, most prominently Parkinson’s disease (PD) and Lewy body dementia (LBD). Co-regulating FA synthesis and degradation proved additive in rescuing PD phenotypes, signifying co-targeting as a therapeutic strategy. LIPE reduction in vivo alleviated αS-induced dopaminergic neurodegeneration in Caenorhabditis elegans. LIPE inhibitors decreased pSer129 and restored tetramer:monomer equilibrium in αS E46K-expressing human neurons. LIPE inhibition rescued all these and the abnormal unfolded protein response. corrected neurons had increased pSer129 and insoluble αS and decreased αS tetramer:monomer ratios. Decreasing LIPE in human neural cells reduced αS inclusions.

Here, we identify the rate-limiting lipase enzyme, LIPE, as a candidate target. However, lipid degradation also generates FA pools. We identified the PD-relevant target stearoyl-coA desaturase: inhibiting monounsaturated FA synthesis reversed PD phenotypes. Although the PD-causing protein α-synuclein (αS) interacts with lipids and fatty acids (FA) physiologically and pathologically, targeting FA homeostasis for therapeutics is in its infancy. Synucleinopathy (Parkinson’s disease (PD) Lewy body dementia) disease-modifying treatments represent a huge unmet medical need.

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