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.

Controlling Cholesterol Synthesis beyond 3-Hydroxy-3-methylglutaryl-CoA Reductase (HMGCR)

“…Additionally, the yeast equivalent of SM, Erg1p, was inactive in lipid droplets (68). Furthermore, in a toxin-induced dopaminergic neuron model of Parkinson disease, LS redistributed from the ER to mitochondria, and the product lanosterol was reduced (69), again suggesting that enzyme translocation reduces flux through the cholesterol synthesis pathway.…”

Dietary cholesterol, fats and risk of Parkinson's disease in the Singapore Chinese Health Study

“…Remarkably, exogenous addition of lanosterol rescued dopaminergic neurons from 1-methyl-4-pheylpyridium (MPP+) induced cell death in culture, suggesting a neuroprotective effect. 32 It has also been found that there is significantly lower cholesterol biosynthesis in patients with PD than controls. 33 While these findings suggest an important role of cholesterol in the pathogenesis or in providing neuroprotection in PD, it is important to note that because plasma lipoproteins do not cross the intact blood-brain barrier, nearly all cholesterol in the brain is synthesised in situ.…”

Morphometric assessment of toxicant induced neuronal degeneration in full and restricted contact co-cultures of embryonic cortical rat neurons and astrocytes: Using m-Dinitrobezene as a model neurotoxicant

“…18, 20, 21 In one such study, IL-1β, a pro-inflammatory cytokine, inhibited axonal growth of developing neurons, suggesting that inflammation may be important in the regulation of neuronal development. 20 Models of neuropathological disorders developed with the aid of compartmentalized devices, include Alzheimer’s disease, 22 Parkinson’s disease (PD), 23 ischemia, 24 glutamate excitotoxicity, 25 and peripheral neuropathy. 26 These devices can be used to clearly visualize and quantity trafficking of molecules or the occurrence of cellular processes, such as mitography, 23 within neurites of afflicted neurons.…”