Dysregulated brain creatine kinase is associated with hearing impairment in mouse models of Huntington disease
Yow-Sien Lin, … , Chih-Hung Wang, Yijuang Chern
Yow-Sien Lin, … , Chih-Hung Wang, Yijuang Chern
Published March 14, 2011
Citation Information: J Clin Invest. 2011;121(4):1519-1523. https://doi.org/10.1172/JCI43220.
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Brief Report Neuroscience

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

Yow-Sien Lin, Chiung-Mei Chen, Bing-wen Soong, Yih-Ru Wu, Hui-Mei Chen, Wen-Ying Yeh, Dai-Rong Wu, Yi-Jun Lin, Paul Wai-Fung Poon, Mei-Ling Cheng, Chih-Hung Wang, Yijuang Chern

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Figure 3

Beneficial effects of creatine supplementation on auditory dysfunction in HD mice.

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Beneficial effects of creatine supplementation on auditory dysfunction i...
Male mice (WT, control diet, n = 18; R6/2, control diet, n = 15; and R6/2 mice, 2% creatine [Cr], n = 11) were fed the indicated diet from the age of 4 weeks. The ABR thresholds upon application of click stimuli (A) or tone-burst stimuli (B) to the indicated mice at the age of 10.5 weeks are shown. (C) Total lysates were harvested from cochlea at the age of 10.5 weeks. Expression of the CKB protein was determined using Western blot analyses and normalized to that of actin as an internal control. Quantitative data are shown in the right panel. Immunostaining of the organ of Corti (D) and spiral ganglion (E) of WT and R6/2 mice (10.5 weeks of age) was conducted to determine the expression of SDH-A (green) and NIIs (red). Scale bars (D and E): 10 μm. Quantitative analyses are shown in the right panels. Data are presented as the mean ± SEM. **P < 0.01 and ***P < 0.001.