title: Dysregulated brain creatine kinase is associated with hearing impairment in mouse models of Huntington disease.
abstract: Huntington disease (HD) is a degenerative disorder caused by expanded CAG repeats in exon 1 of the huntingtin gene (HTT). Patients with late-stage HD are known to have abnormal auditory processing, but the peripheral auditory functions of HD patients have yet to be thoroughly assessed. In this study, 19 HD patients (aged 40-59 years) were assessed for hearing impairment using pure-tone audiometry and assessment of auditory brainstem responses (ABRs). PTA thresholds were markedly elevated in HD patients. Consistent with this, elevated ABR thresholds were also detected in two mouse models of HD. Hearing loss thus appears to be an authentic symptom of HD. Immunohistochemical analyses demonstrated the presence of mutant huntingtin that formed intranuclear inclusions in the organ of Corti of HD mice, which might interfere with normal auditory function. Quantitative RT-PCR and Western blot analyses further revealed reduced expression of brain creatine kinase (CKB), a major enzyme responsible for ATP regeneration via the phosphocreatine-creatine kinase (PCr-CK) system, in the cochlea of HD mice. Treatment with creatine supplements ameliorated the hearing impairment of HD mice, suggesting that the impaired PCr-CK system in the cochlea of HD mice may contribute to their hearing impairment. These data also suggest that creatine may be useful for treating the hearing abnormalities of patients with HD.
authors.affiliation: Molecular Medicine Program, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Yow-Sien
authors.initials: YS
authors.lastname: Lin
authors.forename: Chiung-Mei
authors.initials: CM
authors.lastname: Chen
authors.forename: Bing-wen
authors.initials: BW
authors.lastname: Soong
authors.forename: Yih-Ru
authors.initials: YR
authors.lastname: Wu
authors.forename: Hui-Mei
authors.initials: HM
authors.lastname: Chen
authors.forename: Wen-Ying
authors.initials: WY
authors.lastname: Yeh
authors.forename: Dai-Rong
authors.initials: DR
authors.lastname: Wu
authors.forename: Yi-Jun
authors.initials: YJ
authors.lastname: Lin
authors.forename: Paul Wai-Fung
authors.initials: PW
authors.lastname: Poon
authors.forename: Mei-Ling
authors.initials: ML
authors.lastname: Cheng
authors.forename: Chih-Hung
authors.initials: CH
authors.lastname: Wang
authors.forename: Yijuang
authors.initials: Y
authors.lastname: Chern
mesh_terms: D000328:Adult; D000818:Animals; D001301:Audiometry, Pure-Tone; D015153:Blotting, Western; D016022:Case-Control Studies; D003051:Cochlea / Q000187:drug effects / Q000201:enzymology; D003401:Creatine / Q000494:pharmacology; D052276:Creatine Kinase, BB Form / Q000235:genetics*; D004195:Disease Models, Animal; D016057:Evoked Potentials, Auditory, Brain Stem; D005260:Female; D015870:Gene Expression; D034381:Hearing Loss / Q000188:drug therapy / Q000201:enzymology* / Q000209:etiology / Q000235:genetics*; D006801:Humans; D006816:Huntington Disease / Q000150:complications / Q000201:enzymology* / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D052276:Creatine Kinase, BB Form; D003401:Creatine