Huntington’s disease: neurophysiological insights into molecular mechanisms, disease models, and therapeutic strategies

Huntington’s disease (HD) is a progressive inherited neurodegenerative disorder characterized by motor, cognitive, and psychiatric symptoms. It is caused by an expanded CAG trinucleotide repeat in HTT, which leads to the production of a mutant huntingtin protein (mHTT) with an abnormally long polyglutamine tract. This mutation results in protein misfolding, aggregation, and neuronal toxicity, particularly in the basal ganglia. Symptomatic treatments, such as tetrabenazine for chorea and antipsychotics for psychiatric symptoms, offer some relief, but do not alter the underlying disease progression. Recent studies have focused on understanding the molecular pathology of HD and developing gene therapies that target its genetic cause. Advanced techniques, such as CRISPR-Cas9 and RNA interference (RNAi), aim to reduce or correct mHTT expression, and preclinical studies have demonstrated improvements in motor and cognitive functions in animal models. Gene replacement therapy using viral vectors and lipid nanoparticles is also under investigation, along with potential cell-based therapies to replace lost neurons. Despite promising advances, challenges in delivering therapies across the blood-brain barrier, ensuring long-term safety, and addressing ethical concerns remain significant. Future strategies, such as personalized medicine and targeted gene-editing technologies, are being actively explored as potential disease-modifying approaches capable of altering the progression of HD. Ongoing research is critical for transforming these innovative strategies into clinical treatments, providing new hope for improved outcomes and quality of life in HD patients.