Browsing by Author "Liu, Lei"

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    Lipase regulation of cellular fatty acid homeostasis as a Parkinson's disease therapeutic strategy
    (Nature Portfolio, 2022) Fanning, Saranna; Cirka, Haley; Thies, Jennifer L.; Jeong, Jooyoung; Niemi, Sarah M.; Yoon, Joon; Ho, Gary P. H.; Pacheco, Julian A.; Dettmer, Ulf; Liu, Lei; Clish, Clary B.; Hodgetts, Kevin J.; Hutchinson, John N.; Muratore, Christina R.; Caldwell, Guy A.; Caldwell, Kim A.; Selkoe, Dennis; Harvard University; Brigham & Women's Hospital; Harvard Medical School; University of Alabama Tuscaloosa; Harvard T.H. Chan School of Public Health; Massachusetts Institute of Technology (MIT); Broad Institute
    Synucleinopathy (Parkinson's disease (PD); Lewy body dementia) disease-modifying treatments represent a huge unmet medical need. Although the PD-causing protein alpha-synuclein (alpha S) 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 alpha S inclusions. Patient alpha S triplication vs. corrected neurons had increased pSer129 and insoluble alpha S and decreased alpha S tetramer:monomer ratios. LIPE inhibition rescued all these and the abnormal unfolded protein response. LIPE inhibitors decreased pSer129 and restored tetramer:monomer equilibrium in alpha S E46K-expressing human neurons. LIPE reduction in vivo alleviated alpha S-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.