Enhanced Na + ‐K + ‐2Cl ‐ cotransporter 1 underlies motor dysfunction in huntington's disease

Autor: Yijuang Chern, Ya-Gin Chang, Yi Ting Hsu, Sung‐Sen Yang, Ding‐Jin Lee, Hui-Mei Chen, Chon-Haw Tsai, Yu Chao Liu, Cheng Chang Lien, Kai‐Yi Wang
Rok vydání: 2019
Předmět:
Zdroj: Movement Disorders. 34:845-857
ISSN: 1531-8257
0885-3185
Popis: Background Altered γ-aminobutyric acid signaling is believed to disrupt the excitation/inhibition balance in the striatum, which may account for the motor symptoms of Huntington's disease. Na-K-2Cl cotransporter-1 is a key molecule that controls γ-aminobutyric acid-ergic signaling. However, the role of Na-K-2Cl cotransporter-1 and efficacy of γ-aminobutyric acid-ergic transmission remain unknown in Huntington's disease. Methods We determined the levels of Na-K-2Cl cotransporter-1 in brain tissue from Huntington's disease mice and patients by real-time quantitative polymerase chain reaction, western blot, and immunocytochemistry. Gramicidin-perforated patch-clamp recordings were used to measure the Eγ-aminobutyric acid in striatal brain slices. To inhibit Na-K-2Cl cotransporter-1 activity, R6/2 mice were treated with an intraperitoneal injection of bumetanide or adeno-associated virus-mediated delivery of Na-K-2Cl cotransporter-1 short-hairpin RNA into the striatum. Motor behavior assays were employed. Results Expression of Na-K-2Cl cotransporter-1 was elevated in the striatum of R6/2 and Hdh150Q/7Q mouse models. An increase in Na-K-2Cl cotransporter-1 transcripts was also found in the caudate nucleus of Huntington's disease patients. Accordingly, a depolarizing shift of Eγ-aminobutyric acid was detected in the striatum of R6/2 mice. Expression of the mutant huntingtin in astrocytes and neuroinflammation were necessary for enhanced expression of Na-K-2Cl cotransporter-1 in HD mice. Notably, pharmacological or genetic inhibition of Na-K-2Cl cotransporter-1 rescued the motor deficits of R6/2 mice. Conclusions Our findings demonstrate that aberrant γ-aminobutyric acid-ergic signaling and enhanced Na-K-2Cl cotransporter-1 contribute to the pathogenesis of Huntington's disease and identify a new therapeutic target for the potential rescue of motor dysfunction in patients with Huntington's disease. © 2019 International Parkinson and Movement Disorder Society.
Databáze: OpenAIRE
Externí odkaz: