The pathogenesis of Huntington's disease (HD) involves a complex interplay of genetic, molecular, and cellular mechanisms that ultimately lead to neurodegeneration in specific regions of the brain. HD is caused by a mutation in the HTT gene, located on chromosome 4. This mutation involves an abnormal expansion of a trinucleotide repeat sequence, known as CAG, within the gene. The CAG repeat encodes a polyglutamine tract in the huntingtin protein. The mutant huntingtin protein (mHTT) has an expanded polyglutamine tract, which is toxic to neurons and disrupts normal cellular functions. The expanded polyglutamine tract in mHTT leads to the misfolding and aggregation of the protein. These aggregates, known as inclusion bodies, accumulate within neurons and disrupt cellular processes. Protein aggregation is a hallmark feature of HD pathology and contributes to neuronal dysfunction and death. mHTT disrupts mitochondrial function, leading to impaired energy production, increased oxidative stress, and mitochondrial fragmentation. Mitochondrial dysfunction contributes to neuronal vulnerability and exacerbates neurodegeneration in HD. Dysregulation of glutamate signaling and excitotoxicity play a role in HD pathogenesis. mHTT disrupts glutamate homeostasis, leading to excessive glutamate release and activation of NMDA receptors. Prolonged activation of NMDA receptors results in calcium influx, mitochondrial dysfunction, and neuronal damage. mHTT interferes with axonal transport, the process by which cellular components are transported along axons. Impaired axonal transport disrupts the delivery of essential proteins and organelles to synapses, leading to synaptic dysfunction and neuronal degeneration. Neuroinflammatory processes contribute to HD pathogenesis and exacerbate neuronal damage. Activation of microglia and astrocytes, the resident immune cells of the CNS, leads to the release of pro-inflammatory cytokines, ROS, and other toxic molecules that contribute to neuronal dysfunction and death. mHTT disrupts gene transcription and expression, leading to widespread alterations in gene expression patterns in affected neurons. Transcriptional dysregulation affects multiple cellular pathways involved in neuronal function, survival, and plasticity, contributing to neurodegeneration in HD. HD pathology affects synaptic function and plasticity, leading to impaired neurotransmission and synaptic loss. Synaptic dysfunction contributes to cognitive and motor impairments in HD and is an early feature of the disease. Certain neuronal populations, particularly those in the striatum and cerebral cortex, are selectively vulnerable to the toxic effects of mHTT. The striatum, which plays a crucial role in motor control and cognition, is severely affected in HD, leading to the characteristic motor and cognitive symptoms of the disease.