Transducer of regulated CREB-binding proteins (TORCs) transcription and function is impaired in Huntingtons disease

    Authors

    R. K. Chaturvedi; T. Hennessey; A. Johri; S. K. Tiwari; D. Mishra; S. Agarwal; Y. S. Kim;M. F. Beal

    Comments

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    Abbreviated Journal Title

    Hum. Mol. Genet.

    Keywords

    CONTROLLING MITOCHONDRIAL BIOGENESIS; R6/2 MOUSE MODEL; KNOCK-IN MICE; MUTANT HUNTINGTIN; TRANSGENIC MICE; MEDIATED TRANSCRIPTION; THERAPEUTIC; TARGET; COACTIVATOR TORC2; METABOLIC-CONTROL; CORTICAL-NEURONS; Biochemistry & Molecular Biology; Genetics & Heredity

    Abstract

    Huntingtons disease (HD) is an incurable neurological disorder caused by an abnormal glutamine repeat expansion in the huntingtin (Htt) protein. In the present studies, we investigated the role of Transducers of Regulated cAMP response element-binding (CREB) protein activity (TORCs) in HD, since TORCs play an important role in the expression of the transcriptional co-regulator peroxisome proliferator-activated receptor gamma coactivator 1 (PGC-1), whose expression is impaired in HD. We found significantly decreased TORC1 expression levels in STHdhQ111 cells expressing mutant Htt, in the striatum of NLS-N171-82Q, R6/2 and HdhQ111 HD transgenic mice and in postmortem striatal tissue from HD patients. TORC1 overexpression in wild-type (WT) and Htt striatal cells increased CREB mRNA and protein levels, PGC-1 promoter activity, mRNA expression of the PGC-1, NRF-1, Tfam and CytC genes, mitochondrial DNA content, mitochondrial activity and mitochondrial membrane potential. TORC1 overexpression also increased the resistance of striatal cells to 3-nitropropionic (3-NP) acid-mediated toxicity. In cultured WT and mutant Htt striatal cells, small hairpin RNA-mediated TORC1 knockdown resulted in decreased PGC-1 expression and increased susceptibility to 3-NP-induced toxicity. Overexpression of PGC-1 partially prevented TORC1 knockdown-mediated increased susceptibility of Htt striatal cells to 3-NP. Specific knockdown of TORC1 in the striatum of NLS-N171-82Q HD transgenic mice induced neurodegeneration. Lastly, knockdown of Htt prevents transcriptional repression of TORC1 and CREB in Htt striatal cells. These findings show that impaired expression and function of TORC1, which results in a reduction in PGC-1, plays an important role in mitochondrial dysfunction in HD.

    Journal Title

    Human Molecular Genetics

    Volume

    21

    Issue/Number

    15

    Publication Date

    1-1-2012

    Document Type

    Article

    Language

    English

    First Page

    3474

    Last Page

    3488

    WOS Identifier

    WOS:000306414900015

    ISSN

    0964-6906

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