The role of Smo-Shh/Gli signaling activation in the prevention of neurological and ageing disorders

Abstract

Sonic hedgehog (Shh) signaling is an essential central nervous system (CNS) pathway involved during embryonic development and later life stages. Further, it regulates cell division, cellular differentiation, and neuronal integrity. During CNS development, Smo-Shh signaling is significant in the proliferation of neuronal cells such as oligodendrocytes and glial cells. The initiation of the downstream signalling cascade through the 7-transmembrane protein Smoothened (Smo) promotes neuroprotection and restoration during neurological disorders. The dysregulation of Smo-Shh is linked to the proteolytic cleavage of GLI (glioma-associated homolog) into GLI3 (repressor), which suppresses target gene expression, leading to the disruption of cell growth processes. Smo-Shh aberrant signalling is responsible for several neurological complications contributing to physiological alterations like increased oxidative stress, neuronal excitotoxicity, neuroinflammation, and apoptosis. Moreover, activating Shh receptors in the brain promotes axonal elongation and increases neurotransmitters released from presynaptic terminals, thereby exerting neurogenesis, anti-oxidation, anti-inflammatory, and autophagy responses. Smo-Shh activators have been shown in preclinical and clinical studies to help prevent various neurodegenerative and neuropsychiatric disorders. Redox signalling has been found to play a critical role in regulating the activity of the Smo-Shh pathway and influencing downstream signalling events. In the current study ROS, a signalling molecule, was also essential in modulating the SMO-SHH gli signaling pathway in neurodegeneration. As a result of this investigation, dysregulation of the pathway contributes to the pathogenesis of various neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD).Thus, Smo-Shh signalling activators could be a potential therapeutic intervention to treat neurocomplications of brain disorders.

Keywords: Ageing, neurocomplications; Gli protein; Neuroprotection, “redox signaling’’and ROS; Smoothened receptor; Sonic hedgehog.