title: Transducer of regulated CREB-binding proteins (TORCs) transcription and function is impaired in Huntington's disease.
abstract: Huntington's 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 1α (PGC-1α), 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-1α promoter activity, mRNA expression of the PGC-1α, 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-1α expression and increased susceptibility to 3-NP-induced toxicity. Overexpression of PGC-1α 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-1α, plays an important role in mitochondrial dysfunction in HD.
authors.affiliation: Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York-Presbyterian Hospital, New York, NY 10065, USA. rajnish@iitr.res.in
authors.forename: Rajnish Kumar
authors.initials: RK
authors.lastname: Chaturvedi
authors.forename: Thomas
authors.initials: T
authors.lastname: Hennessey
authors.forename: Ashu
authors.initials: A
authors.lastname: Johri
authors.forename: Shashi Kant
authors.initials: SK
authors.lastname: Tiwari
authors.forename: Divya
authors.initials: D
authors.lastname: Mishra
authors.forename: Swati
authors.initials: S
authors.lastname: Agarwal
authors.forename: Yoon Seong
authors.initials: YS
authors.lastname: Kim
authors.forename: M Flint
authors.initials: MF
authors.lastname: Beal
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: C519509:Crtc1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D012333:RNA, Messenger; D050486:Serotonin Plasma Membrane Transport Proteins; C493231:Slc6a4 protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors