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Inhibitors of cytochrome c release with therapeutic potential for Huntington's disease.

ABSTRACT: Release of mitochondrial cytochrome c resulting in downstream activation of cell death pathways has been suggested to play a role in neurologic diseases featuring cell death. However, the specific biologic importance of cytochrome c release has not been demonstrated in Huntington's disease (HD). To evaluate the role of cytochrome c release, we screened a drug library to identify new inhibitors of cytochrome c release from mitochondria. Drugs effective at the level of purified mitochondria were evaluated in a cellular model of HD. As proof of principle, one drug was chosen for in depth evaluation in vitro and a transgenic mouse model of HD. Our findings demonstrate the utility of mitochondrial screening to identify inhibitors of cell death and provide further support for the important functional role of cytochrome c release in HD. Given that many of these compounds have been approved by the Food and Drug Administration for clinical usage and cross the blood-brain barrier, these drugs may lead to trials in patients.

SUBMITTER: Wang X

PROVIDER: S-EPMC2632939 | biostudies-other | 2008 Sep

REPOSITORIES: biostudies-other

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Inhibitors of cytochrome c release with therapeutic potential for Huntington's disease.

Wang Xin X Zhu Shan S Pei Zhijuan Z Drozda Martin M Stavrovskaya Irina G IG Del Signore Steven J SJ Cormier Kerry K Shimony Ethan M EM Wang Hongyan H Ferrante Robert J RJ Kristal Bruce S BS Friedlander Robert M RM

The Journal of neuroscience : the official journal of the Society for Neuroscience 20080901 38

Release of mitochondrial cytochrome c resulting in downstream activation of cell death pathways has been suggested to play a role in neurologic diseases featuring cell death. However, the specific biologic importance of cytochrome c release has not been demonstrated in Huntington's disease (HD). To evaluate the role of cytochrome c release, we screened a drug library to identify new inhibitors of cytochrome c release from mitochondria. Drugs effective at the level of purified mitochondria were e ...[more]

PMID: 18799679

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Project description:BackgroundHuntington's disease (HD) is a neurodegenerative disorder characterized by psychiatric symptoms, serious motor and cognitive deficits. Certain pathological changes can already be observed in pre-symptomatic HD (pre-HD) patients; however, the underlying molecular pathogenesis is still uncertain and no effective treatments are available until now. Here, we reanalyzed HD-related differentially expressed genes from the GEO database between symptomatic HD patients, pre-HD individuals, and healthy controls using bioinformatics analysis, hoping to get more insight in the pathogenesis of both pre-HD and HD, and shed a light in the potential therapeutic targets of the disease.MethodsPre-HD and symptomatic HD differentially expressed genes (DEGs) were screened by bioinformatics analysis Gene Expression Omnibus (GEO) dataset GSE1751. A protein-protein interaction (PPI) network was used to select hub genes. Subsequently, Gene Ontology (GO) enrichment analysis of DEGs and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis of hub genes were applied. Dataset GSE24250 was downloaded to verify our hub genes by the Kaplan-Meier method using Graphpad Prism 5.0. Finally, target miRNAs of intersected hub genes involved in pre-HD and symptomatic HD were predicted.ResultsA total of 37 and 985 DEGs were identified in pre-HD and symptomatic HD, respectively. The hub genes, SIRT1, SUZ12, and PSMC6, may be implicated in pre-HD, and the hub genes, FIS1, SIRT1, CCNH, SUZ12, and 10 others, may be implicated in symptomatic HD. The intersected hub genes, SIRT1 and SUZ12, and their predicted target miRNAs, in particular miR-22-3p and miR-19b, may be significantly associated with pre-HD.ConclusionThe PSMC6, SIRT1, and SUZ12 genes and their related ubiquitin-mediated proteolysis, transcriptional dysregulation, and histone metabolism are significantly associated with pre-HD. FIS1, CCNH, and their related mitochondrial disruption and transcriptional dysregulation processes are related to symptomatic HD, which might shed a light on the elucidation of potential therapeutic targets in HD.

Project description:BackgroundHuntington or Huntington's disease (HD) is an autosomal dominant neurodegenerative disease characterised by both progressive motor and cognitive dysfunction; its pathogenic mechanisms remain poorly understood and no treatment can currently slow, stop, or reverse its progression. There is some evidence of metallomic dysfunction in limited regions of the HD brain; we hypothesised that these alterations are more widespread than the current literature suggests and may contribute to pathogenesis in HD.MethodsWe measured the concentrations of eight essential metals (sodium, potassium, magnesium, calcium, iron, zinc, copper, and manganese) and the metalloid selenium across 11 brain regions in nine genetically confirmed, clinically manifest cases of HD and nine controls using inductively-coupled plasma mass spectrometry. Case-control differences were assessed by non-parametric Mann-Whitney U test (p < 0.05), risk ratios, E-values, and effect sizes.FindingsWe observed striking decreases in selenium levels in 11 out of 11 investigated brain regions in HD, with risk ratios and effect sizes ranging 2.3-9.0 and 0.7-1.9, respectively. Increased sodium/potassium ratios were observed in every region (risk ratio = 2.5-8.0; effect size = 1.2-5.8) except the substantia nigra (risk ratio = 0.25; effect size = 0.1). Multiple regions showed increased calcium and/or zinc levels, and localised decreases in iron, copper, and manganese were present in the globus pallidus, cerebellum, and substantia nigra, respectively.InterpretationThe observed metallomic alterations in the HD brain may contribute to several pathogenic mechanisms, including mitochondrial dysfunction, oxidative stress, and blood-brain barrier dysfunction. Selenium supplementation may represent a potential, much-needed therapeutic pathway for the treatment of HD that would not require localised delivery in the brain due to the widespread presence of selenium deficiency in regions that show both high and low levels of neurodegeneration.FundingIn Acknowledgments, includes the Lee Trust, the Endocore Research Trust, Cure Huntington's Disease Initiative, the Oakley Mental Health Research Foundation, the Medical Research Council (MRC), the New Zealand Neurological Foundation, and others.

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Inhibitors of cytochrome c release with therapeutic potential for Huntington's disease.

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Inhibitors of cytochrome c release with therapeutic potential for Huntington's disease.

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