The therapeutic potential of (R)-carvedilol in Huntington's disease through enhancement of autophagy-lysosomal pathway via GSK-3β inhibition.

Huntington's disease (HD) is a neurodegenerative disorder caused by the abnormal expansion of CAG repeats in the huntingtin (Htt) gene, leading to the aggregation of mutant huntingtin protein (mHTT) in cells, particularly in cortical and striatal neurons. This results in involuntary movements, cognitive impairment, and emotional instability. One of the critical pathogenic mechanisms in HD is impaired autophagy, which plays a vital role in cellular homeostasis by degrading damaged organelles and misfolded proteins through the formation of autophagosomes that fuse with lysosomes. However, the aggregation of mHTT disrupts autophagic function, leading to the accumulation of mHTT and exacerbating the disease's pathogenesis. Carvedilol is an established clinical medication used to treat hypertension and congestive heart failure. It exerts protective effects by blocking both β1-and β2-adrenergic receptors, reducing sympathetic nervous activity, and promoting vasodilation through α1-adrenergic blockade. Carvedilol has been shown to possess antioxidant and anti-inflammatory properties. In this study, we demonstrate that (R)-carvedilol promotes the nuclear translocation of the transcription factor binding to IGHM enhancer 3 (TFE3) by reducing glycogen synthase-3β (GSK-3β) activation, which increases the expression of autophagy-related proteins and facilitates the autophagy-lysosomal pathway (ALP), thereby enhancing mHTT degradation. Additionally, systemic administration of (R)-carvedilol improves mHTT degradation, provides neuroprotection, and inhibits gliosis, effectively ameliorating behavioral impairments and improving disease progression. Overall, these findings indicate that (R)-carvedilol has therapeutic potential for managing HD by promoting autophagy, facilitating the clearance of mHTT aggregates, and demonstrating advantageous properties in an HD transgenic mouse model, highlighting its promise as a treatment option for neurodegenerative diseases.