Huntington's disease (HD) is an autosomal dominant progressive neurodegenerative disease that is characterized by a triad of motor, psychiatric and cognitive impairments. There is still no effective therapy to delay or halt the disease progress. The striatum and cortex are two particularly affected brain regions that exhibit dense reciprocal excitatory glutamate and inhibitory gamma-amino butyric acid (GABA) connections. Imbalance between excitatory and inhibitory signalling is known to greatly affect motor and cognitive processes. Emerging evidence supports the hypothesis that disrupted GABAergic circuits underlie HD pathogenesis. In the present review, we focused on the multiple defects recently found in the GABAergic inhibitory system, including altered GABA level and synthesis, abnormal subunit composition and distribution of GABAA receptors and aberrant GABAA receptor-mediated signalling. In particular, the important role of cation–chloride cotransporters (i.e. NKCC1 and KCC2) is discussed. Recent studies also suggest that neuroinflammation contributes significantly to the abnormal GABAergic inhibition in HD. Thus, GABAA receptors and cation–chloride cotransporters are potential therapeutic targets for HD. Given the limited availability of therapeutic treatments for HD, a better understanding of GABAergic dysfunction in HD could provide novel therapeutic opportunities.

The dysregulated GABAergic responses and altered expression levels of GABA receptors and potassium-chloride cotransporter-2 in Huntington's disease mice appear to be authentic and may contribute to the clinical manifestations of Huntington's disease patients. © 2017 International Parkinson and Movement Disorder Society.

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

Ceramides, abundant sphingolipids on the cell membrane, can act as signaling molecules to regulate cellular functions including cell viability. Exogenous ceramide has been shown to exert potent anti-proliferative effects against cancer cells, but little is known about how it affects reactive oxygen species (ROS) in lung cancer cells. In this study, we investigated the effect of N-octanoyl-D-erythro-sphingosine (C8-ceramide) on human non-small-cell lung cancer H1299 cells. Flow cytometry-based assays indicated that C8-ceramide increased the level of endogenous ROS in H1299 cells. Interestingly, the ratio of superoxide dismutases (SODs) SOD1 and SOD2 seem to be regulated by C8-ceramide treatment. Furthermore, the accumulation of cell cycle G1 phase and apoptotic populations in C8-ceramide-treated H1299 cells was observed. The results of the Western blot showed that C8-ceramide causes a dramatically increased protein level of cyclin D1, a critical regulator of cell cycle G1/S transition. These results suggest that C8-ceramide acts as a potent chemotherapeutic agent and may increase the endogenous ROS level by regulating the switch of SOD1 and SOD2, causing the anti-proliferation, and consequently triggering the apoptosis of NSCLC H1299 cells. Accordingly, our works may give a promising strategy for lung cancer treatment in the future.

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Tau hyperphosphorylation favors the formation of neurofibrillary tangles and triggers the gradual loss of neuronal functions in tauopathies, including Alzheimer's disease. Herein, we demonstrated that chronic treatment with an inhibitor (J4) of equilibrative nucleoside transporter 1 (ENT1), which plays a critical role in controlling adenosine homeostasis and purine metabolism in the brain, exerted beneficial effects in a mouse model of tauopathy (Thy-Tau22, Tau22). Chronic treatment with J4 improved spatial memory deficits, mitochondrial dysfunction, synaptic plasticity impairment, and gliosis. Immunofluorescence assays showed that J4 not only reduced Tau hyperphosphorylation but also normalized the reduction in mitochondrial mass and suppressed the abnormal activation of AMP-activated protein kinase (AMPK), a pathogenic feature that is also observed in the brains of patients with tauopathies. Given that AMPK is an important energy sensor, our findings suggest that energy dysfunction is associated with tauopathy and that J4 may exert its protective effect by improving energy homeostasis. Bulk RNA-seq analysis revealed that J4 also mitigated immune signature associated with Tau pathology including C1q upregulation and A1 astrocyte markers. Collectively, our findings suggest that identifying strategies for normalizing energy and neuroimmune dysfunctions in tauopathies through adenosinergic signaling modulation may pave the way for the development of treatments for Alzheimer's disease.