Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Transcription profiling of striata from PGC-1a knockout mice and litter mate controls to understand the roles of PGC-1a.

ABSTRACT: Huntington's Disease (HD) is an inherited neurodegenerative disease caused by a glutamine repeat expansion in huntingtin protein. Transcriptional deregulation and altered energy metabolism have been implicated in HD pathogenesis. We report here that mutant huntingtin causes disruption of mitochondrial function by inhibiting expression of PGC-1a, a transcriptional coactivator that regulates several metabolic processes including mitochondrial biogenesis and respiration. Mutant huntingtin represses PGC-1a gene transcription by associating with the promoter and interfering with the CREB/TAF4-dependent transcriptional pathway critical for the regulation of PGC-1a gene expression. Crossbreeding of PGC-1a knockout mice with HD knock-in mice leads to increased neurodegeneration of striatal neurons and motor abnormalities in the HD mice. Importantly, expression of PGC-1a partially reverses the toxic effects of mutant huntingtin in cultured striatal neurons. Moreover, lentiviral-mediated delivery of PGC-1a in the striatum provides neuroprotection in the transgenic HD mice. These studies suggest a key role for PGC-1a in the control of energy metabolism in the early stages of HD pathogenesis. Experiment Overall Design: Total RNA was extracted from striata of 3 pgc1 KO mice and 3 littermate controls using the RNeasy Mini Kit (Qiagen) according to manufacturer's protocol. Samples were analyzed using RNA 6000 Nano LabChip kit on a 2100 Bioanalyzer (Agilent Technologies) to ensure integrity of RNA.

ORGANISM(S): Mus musculus

SUBMITTER: Dimitri Krainc

PROVIDER: E-GEOD-5786 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Transcriptional repression of PGC-1alpha by mutant huntingtin leads to mitochondrial dysfunction and neurodegeneration.

Cui Libin L Jeong Hyunkyung H Borovecki Fran F Parkhurst Christopher N CN Tanese Naoko N Krainc Dimitri D

Cell 20061001 1

Huntington's disease (HD) is an inherited neurodegenerative disease caused by a glutamine repeat expansion in huntingtin protein. Transcriptional deregulation and altered energy metabolism have been implicated in HD pathogenesis. We report here that mutant huntingtin causes disruption of mitochondrial function by inhibiting expression of PGC-1alpha, a transcriptional coactivator that regulates several metabolic processes, including mitochondrial biogenesis and respiration. Mutant huntingtin repr ...[more]

PMID: 17018277

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Project description:The peroxisome proliferator-activated receptor c coactivator 1 (PGC-1) proteins are key regulators of cellular bioenergetics and are accordingly expressed in tissues with a high energetic demand. For example, PGC-1a and PGC-1b control organ function of brown adipose tissue, heart, brain, liver and skeletal muscle. Surprisingly, despite their prominent role in the control of mitochondrial biogenesis and oxidative metabolism, expression and function of the PGC-1 coactivators in the retina, an organ with one of the highest energy demands per tissue weight, are completely unknown. Moreover, the molecular mechanisms that coordinate energy production with repair processes in the damaged retina remain enigmatic. In the present study, we thus investigated the expression and function of the PGC-1 coactivators in the healthy and the damaged retina. We show that PGC-1a and PGC-1b are found at high levels in different structures of the mouse retina, most prominently in the photoreceptors. Furthermore, PGC-1a knockout mice suffer from a striking deterioration in retinal morphology and function upon detrimental light exposure. Gene expression studies revealed dysregulation of all major pathways involved in retinal damage and apoptosis, repair and renewal in the PGC-1a knockouts. The light-induced increase in apoptosis in vivo in the absence of PGC-1a was substantiated in vitro, where overexpression of PGC-1a evoked strong anti-apoptotic effects. Finally, we found that retinal levels of PGC-1 expression are reduced in different mouse models for retinitis pigmentosa. We demonstrate that PGC-1a is a central coordinator of energy production and, importantly, all of the major processes involved in retinal damage and subsequent repair. Together with the observed dysregulation of PGC-1a and PGC-1b in retinitis pigmentosa mouse models, these findings thus imply that PGC-1a might be an attractive target for therapeutic approaches aimed at retinal degeneration diseases.

Dataset Information

Transcription profiling of striata from PGC-1a knockout mice and litter mate controls to understand the roles of PGC-1a.

Publications

Transcriptional repression of PGC-1alpha by mutant huntingtin leads to mitochondrial dysfunction and neurodegeneration.

Similar Datasets

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