Intertwining Neuropathogenic Impacts of Aberrant Circadian Rhythm and Impaired Neuroregenerative Plasticity in Huntington’s Disease: Neurotherapeutic Significance of Chemogenetics

Abstract

Huntington’s disease (HD) is a progressive neurodegenerative disorder characterized by abnormal progressive involuntary movements, cognitive deficits, sleep disturbances, and psychiatric symptoms. The onset and progression of the clinical symptoms have been linked to impaired adult neurogenesis in the brains of subjects with HD, due to the reduced neurogenic potential of neural stem cells (NSCs). Among various pathogenic determinants, an altered clock pathway appears to induce the dysregulation of neurogenesis in neurodegenerative disorders. Notably, gamma-aminobutyric acid (GABA)-ergic neurons that express the vasoactive intestinal peptide (VIP) in the brain play a key role in the regulation of circadian rhythm and neuroplasticity. While an abnormal clock gene pathway has been associated with the inactivation of GABAergic VIP neurons, recent studies suggest the activation of this neuronal population in the brain positively contributes to neuroplasticity. Thus, the activation of GABAergic VIP neurons in the brain might help rectify the irregular circadian rhythm in HD. Chemogenetics refers to the incorporation of genetically engineered receptors or ion channels into a specific cell population followed by its activation using desired chemical ligands. The recent advancement of chemogenetic-based approaches represents a potential scientific tool to rectify the aberrant circadian clock pathways. Considering the facts, the defects in the circadian rhythm can be rectified by the activation of VIP-expressing GABAergic neurons using chemogenetics approaches. Thus, the chemogenetic-based rectification of an abnormal circadian rhythm may facilitate the neurogenic potentials of NSCs to restore the neuroregenerative plasticity in HD. Eventually, the increased neurogenesis in the brain can be expected to mitigate neuronal loss and functional deficits.

Keywords

• Huntington’s disease
• circadian rhythm
• clock genes
• adult neurogenesis
• chemogenetics