Lipase regulation of cellular fatty acid homeostasis as a Parkinson’s disease therapeutic strategy View Full Text


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Article Info

DATE

2022-06-09

AUTHORS

Saranna Fanning, Haley Cirka, Jennifer L. Thies, Jooyoung Jeong, Sarah M. Niemi, Joon Yoon, Gary P. H. Ho, Julian A. Pacheco, Ulf Dettmer, Lei Liu, Clary B. Clish, Kevin J. Hodgetts, John N. Hutchinson, Christina R. Muratore, Guy A. Caldwell, Kim A. Caldwell, Dennis 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. More... »

PAGES

74

References to SciGraph publications

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    http://scigraph.springernature.com/pub.10.1038/s41531-022-00335-6

    DOI

    http://dx.doi.org/10.1038/s41531-022-00335-6

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1148543463

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/35680956


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