@article {1644026,
	title = {Lipase regulation of cellular fatty acid homeostasis as a Parkinson{\textquoteright}s disease therapeutic strategy},
	journal = {NPJ Parkinsons Dis},
	volume = {8},
	number = {1},
	year = {2022},
	month = {2022 Jun 09},
	pages = {74},
	abstract = {Synucleinopathy (Parkinson{\textquoteright}s disease (PD); Lewy body dementia) disease-modifying treatments represent a huge unmet medical need. 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. We identified the PD-relevant target stearoyl-coA desaturase: inhibiting monounsaturated FA synthesis reversed PD phenotypes. However, lipid degradation also generates FA pools. Here, we identify the rate-limiting lipase enzyme, LIPE, as a candidate target. Decreasing LIPE in human neural cells reduced αS inclusions. Patient αS triplication vs. corrected neurons had increased pSer129 and insoluble αS and decreased αS tetramer:monomer ratios. LIPE inhibition rescued all these and the abnormal unfolded protein response. LIPE inhibitors decreased pSer129 and restored tetramer:monomer equilibrium in αS E46K-expressing human neurons. LIPE reduction in vivo alleviated αS-induced dopaminergic neurodegeneration in Caenorhabditis elegans. Co-regulating FA synthesis and degradation proved additive in rescuing PD phenotypes, signifying co-targeting as a therapeutic strategy.},
	issn = {2373-8057},
	doi = {10.1038/s41531-022-00335-6},
	author = {Fanning, Saranna and Cirka, Haley and Thies, Jennifer L and Jeong, Jooyoung and Niemi, Sarah M and Yoon, Joon and Ho, Gary P H and Pacheco, Julian A and Dettmer, Ulf and Liu, Lei and Clish, Clary B and Hodgetts, Kevin J and Hutchinson, John N and Muratore, Christina R and Caldwell, Guy A and Caldwell, Kim A and Selkoe, Dennis}
}
