Neuroprotective roles of Klotho signaling in Huntington's disease: From molecular insights to clinical translation
4 affiliations
- 1Faculty of Pharmaceutical Sciences, The ICFAI University, Himachal Pradesh, India.
- 2GNA School of Pharmacy, GNA University, Phagwara, Punjab, India.
- 3Indo Global Group of Colleges, New Chandigarh, Abhipur, Punjab, 140109, India.
- 4Preclinical Department, Royal College of Medicine Perak, Universiti Kuala Lumpur (UniKL), Ipoh, Perak, Malaysia.
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.
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BibTeX
@article{gupta2026neuroprotective,
title = {{Neuroprotective roles of Klotho signaling in Huntington's disease: From molecular insights to clinical translation}},
author = {Vrinda Gupta and Dinesh Kumar and Meenu Begam and Prteek Kaur and Anish Sarswa and Risha Kumari and Shweta Agarwal and Neeraj Choudhary and Ravindran Jaganathan},
journal = {IBRO Neuroscience Reports},
year = {2026},
month = oct,
doi = {10.1016/j.ibneur.2026.09.023},
url = {https://doi.org/10.1016/j.ibneur.2026.09.023},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Neuroprotective roles of Klotho signaling in Huntington's disease: From molecular insights to clinical translation
AU - Vrinda Gupta
AU - Dinesh Kumar
AU - Meenu Begam
AU - Prteek Kaur
AU - Anish Sarswa
AU - Risha Kumari
AU - Shweta Agarwal
AU - Neeraj Choudhary
AU - Ravindran Jaganathan
PY - 2026
DA - 2026/10/07
JO - IBRO Neuroscience Reports
DO - 10.1016/j.ibneur.2026.09.023
UR - https://doi.org/10.1016/j.ibneur.2026.09.023
AB - 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.
SN - 2667-2421
ER -