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

Andrews, Katie L.; Josiah, Sunday Solomon; Zhang, Jinwei

doi:10.3390/ijms21239142

Cited by 8 publications

(5 citation statements)

References 151 publications

(396 reference statements)

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“…The C-terminus of KCC2 contains a region called the isotonic (ISO) domain, which is necessary for KCC2 to facilitate GABAergic hyperpolarizing signaling [ 21 ]. Due to its role as a key modulator in inhibitory GABAergic signaling, KCC2 has been implicated in various neuropathological conditions involving inhibitory dysfunction, such as Huntington’s disease, Rett syndrome, spinal cord injury, autism, and epilepsy [ 19 , 22 – 26 ].…”

Section: Kcc2 and Chloride Homeostasismentioning

confidence: 99%

Neuronal K+-Cl- cotransporter KCC2 as a promising drug target for epilepsy treatment

McMoneagle,

Zhou,

Zhang

et al. 2023

Acta Pharmacol Sin

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Epilepsy is a prevalent neurological disorder characterized by unprovoked seizures. γ-Aminobutyric acid (GABA) serves as the primary fast inhibitory neurotransmitter in the brain, and GABA binding to the GABAA receptor (GABAAR) regulates Cl- and bicarbonate (HCO3-) influx or efflux through the channel pore, leading to GABAergic inhibition or excitation, respectively. The neuron-specific K+-Cl- cotransporter 2 (KCC2) is essential for maintaining a low intracellular Cl- concentration, ensuring GABAAR-mediated inhibition. Impaired KCC2 function results in GABAergic excitation associated with epileptic activity. Loss-of-function mutations and altered expression of KCC2 lead to elevated [Cl-]i and compromised synaptic inhibition, contributing to epilepsy pathogenesis in human patients. KCC2 antagonism studies demonstrate the necessity of limiting neuronal hyperexcitability within the brain, as reduced KCC2 functioning leads to seizure activity. Strategies focusing on direct (enhancing KCC2 activation) and indirect KCC2 modulation (altering KCC2 phosphorylation and transcription) have proven effective in attenuating seizure severity and exhibiting anti-convulsant properties. These findings highlight KCC2 as a promising therapeutic target for treating epilepsy. Recent advances in understanding KCC2 regulatory mechanisms, particularly via signaling pathways such as WNK, PKC, BDNF, and its receptor TrkB, have led to the discovery of novel small molecules that modulate KCC2. Inhibiting WNK kinase or utilizing newly discovered KCC2 agonists has demonstrated KCC2 activation and seizure attenuation in animal models. This review discusses the role of KCC2 in epilepsy and evaluates its potential as a drug target for epilepsy treatment by exploring various strategies to regulate KCC2 activity.

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Section: Kcc2 and Chloride Homeostasismentioning

confidence: 99%

Neuronal K+-Cl- cotransporter KCC2 as a promising drug target for epilepsy treatment

McMoneagle,

Zhou,

Zhang

et al. 2023

Acta Pharmacol Sin

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“…Intriguingly, from a pathophysiological perspective, a variety of conditions alter the expression of these chloride transporters, including Alzheimer’s disease [ 175 , 176 ], anaesthesia [ 177 ], autism [ 175 , 178 , 179 ], epilepsy [ 167 , 175 , 180 , 181 , 182 , 183 ], Huntington’s disease [ 175 , 184 , 185 , 186 , 187 ], Rett syndrome [ 178 , 188 ], schizophrenia [ 175 , 189 , 190 ] and traumatic brain and spinal cord injury [ 181 , 191 , 192 , 193 , 194 , 195 ].…”

Section: Inhibitory Neurotransmissionmentioning

confidence: 99%

Inhibitory Synaptic Influences on Developmental Motor Disorders

Fogarty

2023

IJMS

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During development, GABA and glycine play major trophic and synaptic roles in the establishment of the neuromotor system. In this review, we summarise the formation, function and maturation of GABAergic and glycinergic synapses within neuromotor circuits during development. We take special care to discuss the differences in limb and respiratory neuromotor control. We then investigate the influences that GABAergic and glycinergic neurotransmission has on two major developmental neuromotor disorders: Rett syndrome and spastic cerebral palsy. We present these two syndromes in order to contrast the approaches to disease mechanism and therapy. While both conditions have motor dysfunctions at their core, one condition Rett syndrome, despite having myriad symptoms, has scientists focused on the breathing abnormalities and their alleviation—to great clinical advances. By contrast, cerebral palsy remains a scientific quagmire or poor definitions, no widely adopted model and a lack of therapeutic focus. We conclude that the sheer abundance of diversity of inhibitory neurotransmitter targets should provide hope for intractable conditions, particularly those that exhibit broad spectra of dysfunction—such as spastic cerebral palsy and Rett syndrome.

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“…[133][134][135][136] Reduced KCC2 function also contributes to circadian rhythm disruption 137 and age-associated neurodegenerative diseases, such as Alzheimer's and Huntington's disease, through impairment of GABAergic inhibition. 136,138,139 As a result of alternative promoter usage, the Scl12a5 gene produces two proteins, KCC2a and KCC2b which differ in their N-termini. 140 Although both isoforms are widely expressed in the brain, KCC2a expression is low in cortical regions, whereas KCC2b is expressed more highly and more widely.…”

Section: Potential Common Effectorsmentioning

confidence: 99%

“…133–136 Reduced KCC2 function also contributes to circadian rhythm disruption 137 and age-associated neurodegenerative diseases, such as Alzheimer’s and Huntington’s disease, through impairment of GABAergic inhibition. 136,138,139…”

Section: Potential Common Effectorsmentioning

confidence: 99%

Rett and Rett-related disorders: Common mechanisms for shared symptoms?

D’Mello

2023

Exp Biol Med (Maywood)

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Rett syndrome is a neurodevelopmental disorder caused by loss-of-function mutations in the methyl-CpG binding protein-2 (MeCP2) gene that is characterized by epilepsy, intellectual disability, autistic features, speech deficits, and sleep and breathing abnormalities. Neurologically, patients with all three disorders display microcephaly, aberrant dendritic morphology, reduced spine density, and an imbalance of excitatory/inhibitory signaling. Loss-of-function mutations in the cyclin-dependent kinase-like 5 (CDKL5) and FOXG1 genes also cause similar behavioral and neurobiological defects and were referred to as congenital or variant Rett syndrome. The relatively recent realization that CDKL5 deficiency disorder (CDD), FOXG1 syndrome, and Rett syndrome are distinct neurodevelopmental disorders with some distinctive features have resulted in separate focus being placed on each disorder with the assumption that distinct molecular mechanisms underlie their pathogenesis. However, given that many of the core symptoms and neurological features are shared, it is likely that the disorders share some critical molecular underpinnings. This review discusses the possibility that deregulation of common molecules in neurons and astrocytes plays a central role in key behavioral and neurological abnormalities in all three disorders. These include KCC2, a chloride transporter, vGlut1, a vesicular glutamate transporter, GluD1, an orphan-glutamate receptor subunit, and PSD-95, a postsynaptic scaffolding protein. We propose that reduced expression or activity of KCC2, vGlut1, PSD-95, and AKT, along with increased expression of GluD1, is involved in the excitatory/inhibitory that represents a key aspect in all three disorders. In addition, astrocyte-derived brain-derived neurotrophic factor (BDNF), insulin-like growth factor 1 (IGF-1), and inflammatory cytokines likely affect the expression and functioning of these molecules resulting in disease-associated abnormalities.

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

Cited by 8 publications

References 151 publications

Neuronal K+-Cl- cotransporter KCC2 as a promising drug target for epilepsy treatment

Neuronal K+-Cl- cotransporter KCC2 as a promising drug target for epilepsy treatment

Inhibitory Synaptic Influences on Developmental Motor Disorders

Rett and Rett-related disorders: Common mechanisms for shared symptoms?

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