title: Enhancement of brain-type creatine kinase activity ameliorates neuronal deficits in Huntington's disease.
abstract: Huntington's disease (HD) is a hereditary neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin (HTT) gene. Brain-type creatine kinase (CKB) is an enzyme involved in energy homeostasis via the phosphocreatine-creatine kinase system. Although downregulation of CKB was previously reported in brains of HD mouse models and patients, such regulation and its functional consequence in HD are not fully understood. In the present study, we demonstrated that levels of CKB found in both the soma and processes were markedly reduced in primary neurons and brains of HD mice. We show for the first time that mutant HTT (mHTT) suppressed the activity of the promoter of the CKB gene, which contributes to the lowered CKB expression in HD. Exogenous expression of wild-type CKB, but not a dominant negative CKB mutant, rescued the ATP depletion, aggregate formation, impaired proteasome activity, and shortened neurites induced by mHTT. These findings suggest that negative regulation of CKB by mHTT is a key event in the pathogenesis of HD and contributes to the neuronal dysfunction associated with HD. In addition, besides dietary supplementation with the CKB substrate, strategies aimed at increasing CKB expression might lead to the development of therapeutic treatments for HD.
authors: Division of Neuroscience, Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors: Yow-Sien
authors: YS
authors: Lin
authors: Tzu-Hao
authors: TH
authors: Cheng
authors: Chin-Pang
authors: CP
authors: Chang
authors: Hui-Mei
authors: HM
authors: Chen
authors: Yijuang
authors: Y
authors: Chern
mesh_terms: D000818:Animals; D001921:Brain / Q000201:enzymology* / Q000473:pathology; D052276:Creatine Kinase, BB Form / Q000096:biosynthesis* / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D006816:Huntington Disease / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000628:therapy; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000201:enzymology* / Q000473:pathology; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D009419:Nerve Tissue Proteins; D050486:Serotonin Plasma Membrane Transport Proteins; C493231:Slc6a4 protein, mouse; D052276:Creatine Kinase, BB Form