CORTISTATIN AS A NOVEL THERAPEUTIC TARGET FOR HUNTINGTON'S DISEASE MODULATING NEUROINFLAMMATION AND MITOCHONDRIAL INTEGRITY

Huntington's disease (HD) is a progressive neurodegenerative disorder caused by expanded CAG repeats in the Huntingtin gene, with mitochondrial dysfunction, oxidative stress, and neuroinflammation playing central roles in disease progression. Current treatments only address symptoms, highlighting the urgent need for interventions targeting core pathogenic processes. Cortistatin is a neuropeptide with established immunomodulatory and neuroprotective properties, and emerging evidence suggests it may also regulate mitochondrial function. Notably, cortistatin deficiency has been linked to increased systemic and central inflammation, suggesting that impaired cortistatin signaling could worsen neurodegeneration, though its specific role in HD and mitochondrial dynamics remains unexplored. This study reanalyzed public human HD transcriptomic datasets and validated findings in experimental HD models, revealing that cortistatin expression was significantly reduced in HD patient brains and animal models. Using wild-type and cortistatin-deficient mice treated with 3-nitropropionic acid as pharmacological HD models, we found that cortistatin deficiency worsened HD-like motor impairments, neuropathology, and reduced mutant huntingtin-expressing neurons viability. Loss of cortistatin also enhanced inflammatory signaling and disrupted mitochondrial integrity and mitochondria-endoplasmic reticulum contacts in HD striatal neurons. Conversely, cortistatin administration attenuated inflammatory mediators, preserved mitochondrial structure, and reduced oxidative stress. These findings implicate cortistatin deficiency in HD pathophysiology and highlight its role in modulating neuroinflammation and mitochondrial dysfunction. Cortistatin represents a novel therapeutic candidate that addresses fundamental HD processes rather than merely symptomatic outcomes, offering promise for HD and other neurodegenerative disorders characterized by inflammatory activation and mitochondrial impairment. This work was supported by Juan de la Cierva fellowship and PTI+ NEUROAGING (CSIC), Spain.