Enhanced Na+ -K+ -2Cl- cotransporter 1 underlies motor dysfunction in huntington's disease. 2019

Yi-Ting Hsu, and Ya-Gin Chang, and Yu-Chao Liu, and Kai-Yi Wang, and Hui-Mei Chen, and Ding-Jin Lee, and Sung-Sen Yang, and Chon-Haw Tsai, and Cheng-Chang Lien, and Yijuang Chern
PhD Program for Translational Medicine, China Medical University and Academia Sinica, Taipei, Taiwan.

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. 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. 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. 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.

UI MeSH Term Description Entries
D008822 Mice, Transgenic Laboratory mice that have been produced from a genetically manipulated EGG or EMBRYO, MAMMALIAN. Transgenic Mice,Founder Mice, Transgenic,Mouse, Founder, Transgenic,Mouse, Transgenic,Mice, Transgenic Founder,Transgenic Founder Mice,Transgenic Mouse
D009474 Neurons The basic cellular units of nervous tissue. Each neuron consists of a body, an axon, and dendrites. Their purpose is to receive, conduct, and transmit impulses in the NERVOUS SYSTEM. Nerve Cells,Cell, Nerve,Cells, Nerve,Nerve Cell,Neuron
D002421 Caudate Nucleus Elongated gray mass of the neostriatum located adjacent to the lateral ventricle of the brain. Caudatus,Nucleus Caudatus,Caudatus, Nucleus,Nucleus, Caudate
D004195 Disease Models, Animal Naturally-occurring or experimentally-induced animal diseases with pathological processes analogous to human diseases. Animal Disease Model,Animal Disease Models,Disease Model, Animal
D005680 gamma-Aminobutyric Acid The most common inhibitory neurotransmitter in the central nervous system. 4-Aminobutyric Acid,GABA,4-Aminobutanoic Acid,Aminalon,Aminalone,Gammalon,Lithium GABA,gamma-Aminobutyric Acid, Calcium Salt (2:1),gamma-Aminobutyric Acid, Hydrochloride,gamma-Aminobutyric Acid, Monolithium Salt,gamma-Aminobutyric Acid, Monosodium Salt,gamma-Aminobutyric Acid, Zinc Salt (2:1),4 Aminobutanoic Acid,4 Aminobutyric Acid,Acid, Hydrochloride gamma-Aminobutyric,GABA, Lithium,Hydrochloride gamma-Aminobutyric Acid,gamma Aminobutyric Acid,gamma Aminobutyric Acid, Hydrochloride,gamma Aminobutyric Acid, Monolithium Salt,gamma Aminobutyric Acid, Monosodium Salt
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D006816 Huntington Disease A familial disorder inherited as an autosomal dominant trait and characterized by the onset of progressive CHOREA and DEMENTIA in the fourth or fifth decade of life. Common initial manifestations include paranoia; poor impulse control; DEPRESSION; HALLUCINATIONS; and DELUSIONS. Eventually intellectual impairment; loss of fine motor control; ATHETOSIS; and diffuse chorea involving axial and limb musculature develops, leading to a vegetative state within 10-15 years of disease onset. The juvenile variant has a more fulminant course including SEIZURES; ATAXIA; dementia; and chorea. (From Adams et al., Principles of Neurology, 6th ed, pp1060-4) Huntington Chorea,Juvenile Huntington Disease,Akinetic-Rigid Variant of Huntington Disease,Chorea, Chronic Progressive Hereditary (Huntington),Chronic Progressive Hereditary Chorea (Huntington),Huntington Chronic Progressive Hereditary Chorea,Huntington Disease, Akinetic-Rigid Variant,Huntington Disease, Juvenile,Huntington Disease, Juvenile-Onset,Huntington Disease, Late Onset,Huntington's Chorea,Huntington's Disease,Juvenile-Onset Huntington Disease,Late-Onset Huntington Disease,Progressive Chorea, Chronic Hereditary (Huntington),Progressive Chorea, Hereditary, Chronic (Huntington),Akinetic Rigid Variant of Huntington Disease,Chorea, Huntington,Chorea, Huntington's,Huntington Disease, Akinetic Rigid Variant,Huntington Disease, Juvenile Onset,Huntington Disease, Late-Onset,Juvenile Onset Huntington Disease,Late Onset Huntington Disease
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D051379 Mice The common name for the genus Mus. Mice, House,Mus,Mus musculus,Mice, Laboratory,Mouse,Mouse, House,Mouse, Laboratory,Mouse, Swiss,Mus domesticus,Mus musculus domesticus,Swiss Mice,House Mice,House Mouse,Laboratory Mice,Laboratory Mouse,Mice, Swiss,Swiss Mouse,domesticus, Mus musculus
D028021 Sodium-Potassium-Chloride Symporters A subclass of symporters that specifically transport SODIUM; POTASSIUM and CHLORIDE ions across cellular membranes in a tightly coupled electroneutrality process. NKCC Proteins,NKCCs,Sodium-Potassium-Chloride Cotransporters,Na(+), K(+), Cl(-)-Cotransporter,Na-K-Cl-Symporter,Na-K-Cl-Transporter,NaCl-KCl Cotransporter,NaK2Cl Symporter,Sodium, Potassium, Chloride-Cotransporter,Sodium-Potassium-Chloride Cotransporter,Cotransporter, NaCl-KCl,Cotransporter, Sodium-Potassium-Chloride,Na K Cl Symporter,Na K Cl Transporter,NaCl KCl Cotransporter,Sodium Potassium Chloride Cotransporter,Sodium Potassium Chloride Cotransporters,Sodium Potassium Chloride Symporters,Symporter, NaK2Cl

Related Publications

Yi-Ting Hsu, and Ya-Gin Chang, and Yu-Chao Liu, and Kai-Yi Wang, and Hui-Mei Chen, and Ding-Jin Lee, and Sung-Sen Yang, and Chon-Haw Tsai, and Cheng-Chang Lien, and Yijuang Chern
December 2005, Acta oto-laryngologica,
Yi-Ting Hsu, and Ya-Gin Chang, and Yu-Chao Liu, and Kai-Yi Wang, and Hui-Mei Chen, and Ding-Jin Lee, and Sung-Sen Yang, and Chon-Haw Tsai, and Cheng-Chang Lien, and Yijuang Chern
April 2002, American journal of physiology. Cell physiology,
Yi-Ting Hsu, and Ya-Gin Chang, and Yu-Chao Liu, and Kai-Yi Wang, and Hui-Mei Chen, and Ding-Jin Lee, and Sung-Sen Yang, and Chon-Haw Tsai, and Cheng-Chang Lien, and Yijuang Chern
May 2010, Biochemical and biophysical research communications,
Yi-Ting Hsu, and Ya-Gin Chang, and Yu-Chao Liu, and Kai-Yi Wang, and Hui-Mei Chen, and Ding-Jin Lee, and Sung-Sen Yang, and Chon-Haw Tsai, and Cheng-Chang Lien, and Yijuang Chern
January 2015, Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology,
Yi-Ting Hsu, and Ya-Gin Chang, and Yu-Chao Liu, and Kai-Yi Wang, and Hui-Mei Chen, and Ding-Jin Lee, and Sung-Sen Yang, and Chon-Haw Tsai, and Cheng-Chang Lien, and Yijuang Chern
August 2001, Hypertension (Dallas, Tex. : 1979),
Yi-Ting Hsu, and Ya-Gin Chang, and Yu-Chao Liu, and Kai-Yi Wang, and Hui-Mei Chen, and Ding-Jin Lee, and Sung-Sen Yang, and Chon-Haw Tsai, and Cheng-Chang Lien, and Yijuang Chern
August 1990, The American journal of physiology,
Yi-Ting Hsu, and Ya-Gin Chang, and Yu-Chao Liu, and Kai-Yi Wang, and Hui-Mei Chen, and Ding-Jin Lee, and Sung-Sen Yang, and Chon-Haw Tsai, and Cheng-Chang Lien, and Yijuang Chern
September 1996, The American journal of physiology,
Yi-Ting Hsu, and Ya-Gin Chang, and Yu-Chao Liu, and Kai-Yi Wang, and Hui-Mei Chen, and Ding-Jin Lee, and Sung-Sen Yang, and Chon-Haw Tsai, and Cheng-Chang Lien, and Yijuang Chern
August 2006, American journal of physiology. Cell physiology,
Yi-Ting Hsu, and Ya-Gin Chang, and Yu-Chao Liu, and Kai-Yi Wang, and Hui-Mei Chen, and Ding-Jin Lee, and Sung-Sen Yang, and Chon-Haw Tsai, and Cheng-Chang Lien, and Yijuang Chern
January 1994, The American journal of physiology,
Yi-Ting Hsu, and Ya-Gin Chang, and Yu-Chao Liu, and Kai-Yi Wang, and Hui-Mei Chen, and Ding-Jin Lee, and Sung-Sen Yang, and Chon-Haw Tsai, and Cheng-Chang Lien, and Yijuang Chern
February 2006, Nihon rinsho. Japanese journal of clinical medicine,
Copied contents to your clipboard!