HUNTINGTON'S DISEASE

Multiple lines of evidence have implicated neuroinflammation as both a cause and an effect of neurodegeneration in Huntington’s disease (HD). Studies of post mortem human HD brains and HD mouse models have demonstrated that the huntingtin protein (mHTT) has neurotoxic effects due to cell-autonomous defects in neurons and through cell-cell interactions with dysfunctional astrocytes and microglia in the brain. Neurodegeneration has been linked to excitotoxicity caused by ion and neurotransmitter concentrations in the brain, supported by evidence that extracellular levels of these molecules are modulated by astrocyte-specific mechanisms which are impaired in HD. mHTT causes monocytes and microglia to be hyper-reactive in HD patients and mouse models, contributing to neurodegeneration. Key pro-inflammatory players NFkB, IL-6, and TNF-α are implicated with disease progression, and several lines of evidence suggest that these molecules are associated with more severe neurodegeneration. Dysregulation of the NFkB activation pathway in particular is seen in HD neurons, astrocytes, microglia, and monocytes and thus may be a major component of the cellular response to mHTT with therapeutic potential. Collectively, the immune response and neuroinflammation are seen as key aspects of pathogenesis in HD, and multiple lines of evidence suggest that the neuroimmune response is both a cause and effect of neurodegeneration.