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

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dc.contributor.authorFanning, Saranna
dc.contributor.authorCirka, Haley
dc.contributor.authorThies, Jennifer L.
dc.contributor.authorJeong, Jooyoung
dc.contributor.authorNiemi, Sarah M.
dc.contributor.authorYoon, Joon
dc.contributor.authorHo, Gary P. H.
dc.contributor.authorPacheco, Julian A.
dc.contributor.authorDettmer, Ulf
dc.contributor.authorLiu, Lei
dc.contributor.authorClish, Clary B.
dc.contributor.authorHodgetts, Kevin J.
dc.contributor.authorHutchinson, John N.
dc.contributor.authorMuratore, Christina R.
dc.contributor.authorCaldwell, Guy A.
dc.contributor.authorCaldwell, Kim A.
dc.contributor.authorSelkoe, Dennis
dc.contributor.otherHarvard University
dc.contributor.otherBrigham & Women's Hospital
dc.contributor.otherHarvard Medical School
dc.contributor.otherUniversity of Alabama Tuscaloosa
dc.contributor.otherHarvard T.H. Chan School of Public Health
dc.contributor.otherMassachusetts Institute of Technology (MIT)
dc.contributor.otherBroad Institute
dc.date.accessioned2023-09-28T22:04:38Z
dc.date.available2023-09-28T22:04:38Z
dc.date.issued2022
dc.description.abstractSynucleinopathy (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.en_US
dc.format.mediumelectronic
dc.format.mimetypeapplication/pdf
dc.identifier.citationFanning, S., Cirka, H., Thies, J. L., Jeong, J., Niemi, S. M., Yoon, J., Ho, G. P. H., Pacheco, J. A., Dettmer, U., Liu, L., Clish, C. B., Hodgetts, K. J., Hutchinson, J. N., Muratore, C. R., Caldwell, G. A., Caldwell, K. A., & Selkoe, D. (2022). Lipase regulation of cellular fatty acid homeostasis as a Parkinson’s disease therapeutic strategy. In npj Parkinson’s Disease (Vol. 8, Issue 1). Springer Science and Business Media LLC. https://doi.org/10.1038/s41531-022-00335-6
dc.identifier.doi10.1038/s41531-022-00335-6
dc.identifier.orcidhttps://orcid.org/0000-0002-4604-4629
dc.identifier.orcidhttps://orcid.org/0000-0002-9509-119X
dc.identifier.orcidhttps://orcid.org/0000-0002-3383-3792
dc.identifier.orcidhttps://orcid.org/0000-0003-4638-1331
dc.identifier.orcidhttps://orcid.org/0000-0002-8283-9090
dc.identifier.orcidhttps://orcid.org/0000-0001-6676-0107
dc.identifier.orcidhttps://orcid.org/0000-0001-7004-8630
dc.identifier.urihttps://ir.ua.edu/handle/123456789/12296
dc.languageEnglish
dc.language.isoen_US
dc.publisherNature Portfolio
dc.rights.licenseAttribution 4.0 International (CC BY 4.0)
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectHORMONE-SENSITIVE LIPASE
dc.subjectPHOSPHORYLATED ALPHA-SYNUCLEIN
dc.subjectMOLECULAR-WEIGHT COMPLEXES
dc.subjectSTEAROYL-COA DESATURASE
dc.subjectPHOSPHOLIPID-BINDING
dc.subjectLIPID DROPLETS
dc.subjectCAENORHABDITIS-ELEGANS
dc.subjectALZHEIMERS-DISEASE
dc.subjectNEURONS
dc.subjectMUTATION
dc.subjectNeurosciences
dc.titleLipase regulation of cellular fatty acid homeostasis as a Parkinson's disease therapeutic strategyen_US
dc.typeArticle
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