Lipase regulation of cellular fatty acid homeostasis as a Parkinson's disease therapeutic strategy.

Autor: Fanning S; Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA. sfanning2@bwh.harvard.edu., Cirka H; Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA., Thies JL; Department of Biological Sciences, The University of Alabama, Tuscaloosa, AL, 35487, USA., Jeong J; Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA., Niemi SM; Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA., Yoon J; Department of Biostatistics, The Harvard Chan School of Public Health, Boston, MA, 02115, USA., Ho GPH; Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA., Pacheco JA; Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA., Dettmer U; Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA., Liu L; Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA., Clish CB; Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA., Hodgetts KJ; Laboratory for Drug Discovery in Neuroscience, Department of Neurology, Brigham and Women's Hospital, Boston, MA, 02115, USA., Hutchinson JN; Department of Biostatistics, The Harvard Chan School of Public Health, Boston, MA, 02115, USA., Muratore CR; Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA., Caldwell GA; Department of Biological Sciences, The University of Alabama, Tuscaloosa, AL, 35487, USA., Caldwell KA; Department of Biological Sciences, The University of Alabama, Tuscaloosa, AL, 35487, USA., Selkoe D; Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA. dselkoe@bwh.harvard.edu.
Jazyk: angličtina
Zdroj: NPJ Parkinson's disease [NPJ Parkinsons Dis] 2022 Jun 09; Vol. 8 (1), pp. 74. Date of Electronic Publication: 2022 Jun 09.
DOI: 10.1038/s41531-022-00335-6
Abstrakt: 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.
(© 2022. The Author(s).)
Databáze: MEDLINE
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