title: Lanosterol induces mitochondrial uncoupling and protects dopaminergic neurons from cell death in a model for Parkinson's disease.
abstract: Parkinson's disease (PD) is a neurodegenerative disorder marked by the selective degeneration of dopaminergic neurons in the nigrostriatal pathway. Several lines of evidence indicate that mitochondrial dysfunction contributes to its etiology. Other studies have suggested that alterations in sterol homeostasis correlate with increased risk for PD. Whether these observations are functionally related is, however, unknown. In this study, we used a toxin-induced mouse model of PD and measured levels of nine sterol intermediates. We found that lanosterol is significantly (∼50%) and specifically reduced in the nigrostriatal regions of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated mice, indicative of altered lanosterol metabolism during PD pathogenesis. Remarkably, exogenous addition of lanosterol rescued dopaminergic neurons from 1-methyl-4-phenylpyridinium (MPP+)-induced cell death in culture. Furthermore, we observed a marked redistribution of lanosterol synthase from the endoplasmic reticulum to mitochondria in dopaminergic neurons exposed to MPP+, suggesting that lanosterol might exert its survival effect by regulating mitochondrial function. Consistent with this model, we find that lanosterol induces mild depolarization of mitochondria and promotes autophagy. Collectively, our results highlight a novel sterol-based neuroprotective mechanism with direct relevance to PD.
authors.affiliation: Department of Biological Sciences, National University of Singapore, Singapore. g0601115@nus.edu.sg
authors.forename: L
authors.initials: L
authors.lastname: Lim
authors.forename: V
authors.initials: V
authors.lastname: Jackson-Lewis
authors.forename: L C
authors.initials: LC
authors.lastname: Wong
authors.forename: G H
authors.initials: GH
authors.lastname: Shui
authors.forename: A X H
authors.initials: AX
authors.lastname: Goh
authors.forename: S
authors.initials: S
authors.lastname: Kesavapany
authors.forename: A M
authors.initials: AM
authors.lastname: Jenner
authors.forename: M
authors.initials: M
authors.lastname: Fivaz
authors.forename: S
authors.initials: S
authors.lastname: Przedborski
authors.forename: M R
authors.initials: MR
authors.lastname: Wenk
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects; D003342:Corpus Striatum / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007810:Lanosterol / Q000494:pharmacology*; D020267:MPTP Poisoning / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects*; D051379:Mice; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology
chemical_list: D007810:Lanosterol