Lipase regulation of cellular fatty acid homeostasis as a Parkinson’s disease therapeutic strategy
Saranna Fanning, Haley Cirka, Jennifer L. Thies, Jooyoung Jeong, Sarah M. Niemi, Joon Yoon, Gary P. H. Ho, Julián Ávila-Pacheco, Ulf Dettmer, Lei Liu, Clary B. Clish, Kevin J. Hodgetts, John N. Hutchinson, Christina Muratore, Guy A. Caldwell, Kim A. Caldwell, Dennis J. Selkoe
Abstract
Synucleinopathy (Parkinson'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.