Neuroprotective roles of Klotho signaling in Huntington's disease: From molecular insights to clinical translation

Abstract

Huntington's Disease (HD) is an autosomal dominant neurodegenerative disorder caused by CAG repeat expansion in the HTT gene, producing toxic mutant huntingtin (mHTT) protein. This leads to progressive motor dysfunction, cognitive decline, and psychiatric disturbances. Despite advances in understanding mHTT toxicity, potentially disease-modifying therapies remain scarce, underscoring the need for novel approaches targeting core pathophysiological mechanisms. Klotho, a multifunctional anti-aging protein, regulates several pathways relevant to neuronal survival and may have relevance to HD pathophysiology. Klotho is a co-receptor with a membrane and is a soluble co-receptor that regulates synaptic and metabolic homeostasis. Although direct experimental evidence in HD remains limited, emerging findings from aging and neurodegeneration research suggest that Klotho-mediated pathways may influence mechanisms relevant to HD pathogenesis. It suppresses fibroblast growth factor receptor (FGFR) signaling and major pathways such as PI3K/Akt-FOXO, Wnt/ -catenin and insulin/IGF-1 pathways, which oppose the hallmarks of HD, namely excitotoxicity, calcium dysregulation, impaired neuroprotection, and peripheral neuroinflammation. There is growing evidence of the involvement of Klotho in mitochondrial health and biogenesis, mitophagy coordination, and oxidative stress resistance - direct mitigating cellular toxicity caused by mHTT. These mechanistic overlaps suggest that Klotho signaling may represent a potential area for investigation in HD. It deals with oxidative stress, excitotoxicity, inflammation, and metabolic dysregulation, and compares it to other diseases of the neurodegenerative type in which Klotho deficits contribute to pathology. Such a structure encourages Klotho-based interventions as a new, mechanism-based approach to HD. Further experimental studies are required to determine whether modulation of Klotho signaling could influence disease progression in HD.