The Huntingtons Disease pathophysiology explained
Huntington’s disease is a hereditary neurodegenerative disorder characterized by progressive motor dysfunction, cognitive decline, and psychiatric issues. Its pathophysiology is complex, rooted in genetic mutations that lead to widespread neuronal damage, particularly within the basal ganglia and cerebral cortex. Understanding the molecular and cellular mechanisms underlying Huntington’s disease is crucial for developing targeted therapies and improving patient outcomes.
The root cause of Huntington’s disease lies in a genetic mutation involving the HTT gene, which encodes the huntingtin protein. In affected individuals, this gene contains an expanded CAG trinucleotide repeat—more than 36 repeats—resulting in an abnormal version of the protein with an elongated polyglutamine (polyQ) tract. This genetic anomaly is inherited in an autosomal dominant pattern, meaning only one copy of the mutated gene is sufficient to cause the disease.
The expanded polyQ segment causes the huntingtin protein to misfold, aggregate, and form insoluble inclusions within neurons. These aggregates disrupt cellular functions, impairing critical processes such as transcription, mitochondrial function, and proteostasis. The toxic effects of mutant huntingtin lead to neuronal dysfunction and eventual cell death, particularly in the striatum—a key component of the basal ganglia involved in motor control—and the cerebral cortex, responsible for higher cognitive functions.
One of the key mechanisms driving neuronal death in Huntington’s disease is excitotoxicity. The degeneration of medium spiny neurons in the striatum results in disrupted neurotransmitter balance, especially involving gamma-aminobutyric acid (GABA) and dopamine. This imbalance enhances glutamate-mediated excitotoxicity, leading to calcium overload and activation of cell death pathways. Additionally, mitochondrial dysfunction plays a vital role; mutant huntingtin impairs mitochondrial dynamics and energy production, increasing oxidative stress and promoting apoptosis.
Another important aspect of Huntington’s disease pathophysiology is the impairment of cellular clearance mechanisms. Autophagy, the process responsible for degrading and recycling damaged cellular components, is often dysfunctional in affected neurons. This failure leads to the accumulation of toxic protein aggregates, exacerbating neuronal stress and death. Moreover, neuroinflammation appears to contribute to disease progression, with activated microglia releasing inflammatory cytokines that further damage neurons.
The combination of these pathological processes results in the selective vulnerability of certain neuronal populations. The loss of neurons in the striatum manifests clinically as movement abnormalities like chorea, dystonia, and rigidity. Cognitive decline emerges as cortical neurons degenerate, impairing executive functions, memory, and decision-making. Psychiatric symptoms such as depression, irritability, and psychosis also reflect widespread neurochemical and structural changes.
In summary, Huntington’s disease pathophysiology involves a cascade initiated by a genetic mutation that produces a toxic, misfolded huntingtin protein. This leads to protein aggregation, mitochondrial dysfunction, excitotoxicity, and impaired cellular clearance, culminating in neuronal death. Understanding these mechanisms provides insights into potential therapeutic targets aimed at slowing or halting disease progression.
