Abnormal mitochondrial dynamics, mitochondrial loss and mutant huntingtin oligomers in Huntington's disease: implications for selective neuronal damage

The purpose of our study was to determine the relationship between mutant huntingtin (Htt) and mitochondrial dynamics in the progression of Huntington's disease (HD). We measured the mRNA levels of electron transport chain genes, and mitochondrial structural genes, Drp1 (dynamin-related protein...

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Published in:	Human molecular genetics Vol. 20; no. 7; pp. 1438 - 1455
Main Authors:	SHIRENDEB, Ulziibat, REDDY, Arubala P, MANCZAK, Maria, CALKINS, Marcus J, PEIZHONG MAO, TAGLE, Danilo A, HEMACHANDRA REDDYL, P
Format:	Journal Article
Language:	English
Published:	Oxford Oxford University Press 01-04-2011
Subjects:	Axons - metabolism Axons - pathology Biological and medical sciences Biological Transport - genetics Cell Nucleus - metabolism Cell Nucleus - pathology Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases DNA Damage - genetics Electron Transport Chain Complex Proteins - biosynthesis Electron Transport Chain Complex Proteins - genetics Female Frontal Lobe - metabolism Frontal Lobe - pathology Fundamental and applied biological sciences. Psychology Gene Expression Regulation - genetics Genetics of eukaryotes. Biological and molecular evolution Humans Huntingtin Protein Huntington Disease - genetics Huntington Disease - metabolism Huntington Disease - pathology Male Medical sciences Mitochondria - genetics Mitochondria - metabolism Mitochondria - pathology Molecular and cellular biology Nerve Tissue Proteins - genetics Nerve Tissue Proteins - metabolism Neurology Nuclear Proteins - genetics Nuclear Proteins - metabolism Protein Multimerization RNA, Messenger - biosynthesis RNA, Messenger - genetics Nervous system diseases Huntingtin Huntington disease Oligomer Genetic disease Cerebral disorder Mitochondria Neuron Dynamics Central nervous system disease Genetics Degenerative disease Lesion Mutation Extrapyramidal syndrome
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Summary:	The purpose of our study was to determine the relationship between mutant huntingtin (Htt) and mitochondrial dynamics in the progression of Huntington's disease (HD). We measured the mRNA levels of electron transport chain genes, and mitochondrial structural genes, Drp1 (dynamin-related protein 1), Fis1 (fission 1), Mfn1 (mitofusin 1), Mfn2 (mitofusin 2), Opa1 (optric atrophy 1), Tomm40 (translocase of outermembrane 40) and CypD (cyclophilin D) in grade III and grade IV HD patients and controls. The mutant Htt oligomers and the mitochondrial structural proteins were quantified in the striatum and frontal cortex of HD patients. Changes in expressions of the electron transport chain genes were found in HD patients and may represent a compensatory response to mitochondrial damage caused by mutant Htt. Increased expression of Drp1 and Fis1 and decreased expression of Mfn1, Mfn2, Opa1 and Tomm40 were found in HD patients relative to the controls. CypD was upregulated in HD patients, and this upregulation increased as HD progressed. Significantly increased immunoreactivity of 8-hydroxy-guanosine was found in the cortical specimens from stage III and IV HD patients relative to controls, suggesting increased oxidative DNA damage in HD patients. In contrast, significantly decreased immunoreactivities of cytochrome oxidase 1 and cytochrome b were found in HD patients relative to controls, indicating a loss of mitochondrial function in HD patients. Immunoblotting analysis revealed 15, 25 and 50 kDa mutant Htt oligomers in the brain specimens of HD patients. All oligomeric forms of mutant Htt were significantly increased in the cortical tissues of HD patients, and mutant Htt oligomers were found in the nucleus and in mitochondria. The increase in Drp1, Fis1 and CypD and the decrease in Mfn1 and Mfn2 may be responsible for abnormal mitochondrial dynamics that we found in the cortex of HD patients, and may contribute to neuronal damage in HD patients. The presence of mutant Htt oligomers in the nucleus of HD neurons and in mitochondria may disrupt neuronal functions. Based on these findings, we propose that mutant Htt in association with mitochondria imbalance and mitochondrial dynamics impairs axonal transport of mitochondria, decreases mitochondrial function and damages neurons in affected brain regions of HD patients.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0964-6906 1460-2083
DOI:	10.1093/hmg/ddr024