Lanosterol induces mitochondrial uncoupling and protects dopaminergic neurons from cell death in a model for Parkinson's disease
Lynette LimVernice Jackson‐LewisLoo Chin WongGuanghou ShuiAngeline GohSashi KesavapanyAndrew M. JennerMarc FivazSerge PrzedborskiMarkus R. Wenk
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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.Keywords:
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Abstract: 1‐Methyl‐3‐phenyl‐1,2,3,6‐tetrahydropyridine (M‐3‐PTP) is an analogue to the Parkinson‐producing dopaminergic toxin 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP). M‐3‐PTP, and simple analogues thereof, are versatile intermediates in organic synthesis. The present study was undertaken to investigate the possible dopaminergic toxicity of M‐3‐PTP. Male albino mice were injected with 50 mg/kg of either MPTP or M‐3‐PTP and dopamine (DA) and its metabolites were determined 2 hr and 7 days after the administration. Two hr after MPTP profound acute changes in brain DA metabolism were found, i.e. an approximately 50% reduction in the concentration of DA together with a 10‐fold increase in the level of 3‐methoxytyramine. Seven days after MPTP, DA and metabolites were markedly reduced which is consistent with a degeneration of the dopaminergic neurones. In contrast M‐3‐PTP produced no acute or long‐term alterations in the concentrations of DA and its metabolites in mouse brain. Furthermore, in vitro experiments show that M‐3‐PTP does not inhibit monoamine oxidase B. Thus, the present data show that M‐3‐PTP is devoid of dopaminergic toxicity in mouse brain and is not likely to produce Parkinson's disease in humans. The lack of toxicity is probably explained by the low affinity of M‐3‐PTP for monoamino oxidase B.
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Abstract The sterol composition of Pneumocystis carinii , an opportunistic pathogen responsible for life‐threatening pneumonia in immunocompromised patients, was determined. Our purpose was to identify pathway‐specific enzymes to impair using sterol biosynthesis inhibitors. Prior to this study, cholesterol 15 ( ca. 80% of total sterols), lanosterol 1 , and several phytosterols common to plants (sitosterol 31 , 24α‐ethyl and campesterol, 24α‐methyl 30 ) were demonstrated in the fungus. In this investigation, we isolated all the previous sterols and many new compounds from P. carinii by culturing the microorganism in steroid‐immunosuppressed rats. Thirty‐one sterols were identified from the fungus (total sterol=100 fg/cell), and seven sterols were identified from rat chow. Unusual sterols in the fungus not present in the diet included, 24(28)‐methylenelanosterol 2 ; 24(28) E ‐ethylidene lanosterol 3 ; 24(28) Z ‐ethylidene lanosterol 4 ; 24β‐ethyllanosta‐25(27)‐dienol 5 ; 24β‐ethylcholest‐7‐enol 6 ; 24β‐ethylcholesterol 7 ; 24β‐ethylcholesta‐5,25(27)‐dienol 8 ; 24‐methyllanosta‐7‐enol 9 ; 24‐methyldesmosterol 10 ; 24(28)‐methylenecholest‐7‐enol 11 ; 24β‐methylcholest‐7‐enol 12 ; and 24β‐methylcholesterol 13 . The structural relationships of the 24‐alkyl groups in the sterol side chain were demonstrated chromatographically relative to authentic specimens, by MS and high‐resolution 1 H NMR. The hypothetical order of these compounds poses multiple phytosterol pathways that diverge from a common intermediate to generate 24β‐methyl sterols: route 1, 1→2→11→12→13 ; route 2, 1→2→9→10→13 ; or 24β‐ethyl sterols: route 3, 1→2→4→6→7 ; route 4, 1→2→5→8→7 . Formation of 3 is considered to form an interrupted sterol pathway. Taken together, operation of distinct sterol methyl transferase (SMT) pathways that generate 24β‐alkyl sterols in P. carinii with no counterpart in human biochemistry suggests a close taxonomic affinity with fungi and provides a basis for mechanism‐based inactivation of SMI enzyme to treat Pneumocystis pneumonia.
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