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

Abstract

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

The Therapeutic Potential of Neuronal K-Cl Co-Transporter KCC2 in Huntington’s Disease and Its Comorbidities

“…This extensive study revealed the mechanisms involved in NKCC1 molecular transportation and communication and further provided insights into ion selectivity as well as coupling and translocation; a clearer framework for understanding the physiological functions of NKCC1 in relation to human diseases was also established [57]. Besides, modulation of NKCC1 activity alongside that of KCC2 has been implicated in the development and progression of HD [2,[58][59][60]. These CCCs are differentially expressed over the course of development, and so the activity of KCC2 and NKCC1 is not synonymous between immature and mature neurons [50].…”

“…Importantly, the inhibition/stimulation of KCC2/NKCC1 pair via protein phosphorylation is through a regulatory mechanism that works in a reciprocal pattern [53,64] and members of the with-no-lysine kinase (WNKs) family as well as their downstream targets; STE20/SPS1-related proline/alanine rich kinase (SPAK) and oxidative stress response kinase (OSR1) are the most prominent kinases that regulate this process [52,[64][65][66][67]. Consequently, impaired ion homeostasis resulting from mutation in the physiological function of some of this transporter pair and/or their upstream regulators may be detrimental and subsequently result in diminished inhibition and augmented network hyperexcitability, which underlies numerous neurological disorders [52,66,[68][69][70][71] including HD [58][59][60].…”

“…When [Cl − ] i exceeds equilibrium, depolarisation events contribute to the onset of neurological disease [35,46]. Decreased KCC2 expression coupled with increased NKCC1 expression and/or activity has been documented in several pathologies [63,68,69,71], including HD [58][59][60]. In HD, HTT is mutated (mHTT) and acts to alter KCC2 and NKCC1 expressions and activity [58,59] through mechanisms that remain undetermined.…”

“…Decreased KCC2 expression coupled with increased NKCC1 expression and/or activity has been documented in several pathologies [63,68,69,71], including HD [58][59][60]. In HD, HTT is mutated (mHTT) and acts to alter KCC2 and NKCC1 expressions and activity [58,59] through mechanisms that remain undetermined. Since KCC2 and NKCC1 expressions and functionality are crucial in determining the effects of GABA dysregulated KCC2 and NKCC1 activities [32,46,58,72], subsequent abnormalities in GABAergic signalling are thought to contribute to HD pathogenesis [2].…”

“…In HD, HTT is mutated (mHTT) and acts to alter KCC2 and NKCC1 expressions and activity [58,59] through mechanisms that remain undetermined. Since KCC2 and NKCC1 expressions and functionality are crucial in determining the effects of GABA dysregulated KCC2 and NKCC1 activities [32,46,58,72], subsequent abnormalities in GABAergic signalling are thought to contribute to HD pathogenesis [2]. Hence, this review aims to investigate the possible mechanisms by which KCC2 expression and function is altered in HD.…”