Disruption of immune cell function by mutant huntingtin in Huntington's disease pathogenesis

• Neurodegeneration is accompanied by central and systemic inflammation.
• Innate immune cell function is perturbed in Huntington's disease (HD).
• This dysfunction is largely due to the cell autonomous effects of mutant huntingtin.
• Systemic inflammation may act as a modifier of HD onset and/or progression.
• Targeting innate immune cells offers opportunities for therapeutic intervention in HD.

Innate immune dysfunction is increasingly recognised as a key characteristic of neurodegenerative disease. In the fatal inherited neurological disorder, Huntington's disease, altered innate immune cell function and increased inflammation are observed in the brain and the periphery of disease gene carriers many years before symptom onset, suggesting a potentially early and important role in disease pathogenesis. This is due, at least in part, to the intrinsic effects of the disease-causing protein, mutant huntingtin, expressed in innate immune cells themselves. Understanding whether such innate immune dysfunction in Huntington's disease can be targeted to slow the onset and/or the progression of the disease has significant therapeutic implications and is the subject of much current research.