Polyamines signalling pathway: A key player in unveiling the molecular mechanisms underlying Huntington's disease.

Polyaminesare essential organic cations found in all eukaryotic cells and play an important role in many cellular processes including growth, differentiation, andneuroprotection. This review explores the complex relationship between polyamine signaling and Huntington's disease (HD), an autosomal-dominant neurodegenerative disorder characterized by the progressive degeneration of medium-spiny neurons in the striatum and cortex due to mutations in the huntingtin gene. We provide a comprehensive overview of how polyamines, specificallyputrescine,spermidine, andspermine, regulate important cellular functions such as gene expression, protein synthesis, membrane stability, and ion channel regulation with implications for HD. Dysfunction in polyamine metabolism in HD, reveals how changes in these molecules promote oxidative stress, mitochondrial dysfunction, andexcitotoxicity. Importantly, polyamines interact with mutanthuntingtin protein (mHTT) to affect its aggregationand neurotoxicity. This effect may contribute to the pathophysiological mechanisms underlying HD, suggesting that polyamines may act as potential biomarkers of disease progression. Additionally, we discuss the therapeutic implications of targeting the polyamine signaling pathway to alleviate HD symptoms. By enhancing autophagy and modulating neurotransmitter systems, polyamines mayprovideneuroprotectionagainstmHTT-inducedtoxicity. Moreover, the present review provides new insight into the role of polyamines in the pathogenesis of HDand suggests that regulation of polyamine metabolism may represent a promising therapy to slow the disease progression. Besides this, the review highlights the need for further investigation of the diverse roles of polyamines in neurodegenerative diseases, including HD, paving the way for novel interventions to improve cellular homeostasis andpatient outcomes.