Unbiased gene expression analysis implicates the huntingtin polyglutamine tract in extra-mitochondrial energy metabolism
| Autor: | Marcy E. MacDonald, Elena Ivanova, Isaac S. Kohane, Tanya Cashorali, Ihn Sik Seong, Jong-Min Lee, James F. Gusella |
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| Rok vydání: | 2007 |
| Předmět: |
Cancer Research
congenital hereditary and neonatal diseases and abnormalities Huntingtin lcsh:QH426-470 Respiratory chain Mice Transgenic Nerve Tissue Proteins Biology Mitochondrion medicine.disease_cause 03 medical and health sciences Mice 0302 clinical medicine SETD2 mental disorders medicine Genetics Animals Cluster Analysis Humans NRF1 Molecular Biology Genetics (clinical) Ecology Evolution Behavior and Systematics Cells Cultured 030304 developmental biology Oligonucleotide Array Sequence Analysis Regulation of gene expression Mutation 0303 health sciences Huntingtin Protein Gene Expression Profiling Nuclear Proteins Genetics and Genomics Polyglutamine tract Mus (Mouse) Molecular biology 3. Good health Mitochondria lcsh:Genetics Gene Expression Regulation Energy Metabolism Peptides 030217 neurology & neurosurgery Metabolic Networks and Pathways Research Article |
| Zdroj: | PLoS Genetics PLoS Genetics, Vol 3, Iss 8, p e135 (2007) |
| ISSN: | 1553-7404 |
| Popis: | The Huntington's disease (HD) CAG repeat, encoding a polymorphic glutamine tract in huntingtin, is inversely correlated with cellular energy level, with alleles over ∼37 repeats leading to the loss of striatal neurons. This early HD neuronal specificity can be modeled by respiratory chain inhibitor 3-nitropropionic acid (3-NP) and, like 3-NP, mutant huntingtin has been proposed to directly influence the mitochondrion, via interaction or decreased PGC-1α expression. We have tested this hypothesis by comparing the gene expression changes due to mutant huntingtin accurately expressed in STHdhQ111/Q111 cells with the changes produced by 3-NP treatment of wild-type striatal cells. In general, the HD mutation did not mimic 3-NP, although both produced a state of energy collapse that was mildly alleviated by the PGC-1α-coregulated nuclear respiratory factor 1 (Nrf-1). Moreover, unlike 3-NP, the HD CAG repeat did not significantly alter mitochondrial pathways in STHdhQ111/Q111 cells, despite decreased Ppargc1a expression. Instead, the HD mutation enriched for processes linked to huntingtin normal function and Nf-κB signaling. Thus, rather than a direct impact on the mitochondrion, the polyglutamine tract may modulate some aspect of huntingtin's activity in extra-mitochondrial energy metabolism. Elucidation of this HD CAG-dependent pathway would spur efforts to achieve energy-based therapeutics in HD. Author Summary Huntington's disease (HD) is a tragic neurodegenerative disorder caused by a CAG repeat that specifies the size of a glutamine tract in the huntingtin protein, such that the longer the tract, the earlier the loss of striatal brain cells. A correlation of polyglutamine tract size has also implicated huntingtin in the proper functioning of mitochondria, the cell's energy factories. Here we have tested the prevailing hypothesis, that huntingtin may directly affect the mitochondrion, by using comprehensive gene expression analysis to judge whether the HD mutation may replicate the effects of 3-nitropropionic acid (3-NP), a compound known to inhibit mitochondria, with loss of striatal neurons. We found that, while mutant huntingtin and 3-NP both elicited energy starvation, the gene responses to the HD mutation, unlike the responses to 3-NP, did not highlight damage to mitochondria, but instead revealed effects on huntingtin-dependent processes. Thus, rather than direct inhibition, the polyglutamine tract size appears to modulate some normal activity of huntingtin that indirectly influences the management of the mitochondrion. Understanding the precise nature of this extra-mitochondrial process would critically guide efforts to achieve effective energy-based therapeutics in HD. |
| Databáze: | OpenAIRE |
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