Immune cells as well as brain cells are affected in Huntington's disease - and the two may be closely connected.
The brain is the main focus of Huntington's disease, but the mutant protein that causes it is present in every cell of the body. Indeed, abnormalities have been identified outside the brain, particularly in the immune system. Professor Sarah Tabrizi and colleagues have identified a key mechanism by which the Huntington's mutation leads to overactive innate immune responses, a finding that could have consequences for the brain as well as peripheral tissues.
Huntington's disease is caused by the expansion of a three-nucleotide repeat in the gene for huntingtin, a protein of poorly understood function. The mutation leads to a protein with a run of additional glutamine residues. As well as effects on the brain, mutant huntingtin is known to have a wider impact, causing muscle wasting and weight loss, despite increased calorie intake, and neuroendocrine changes.
Indeed, in 2008, Professor Tabrizi showed that Huntington's disease is associated with elevated levels of a particular cytokine, IL-6, associated with activation of the innate immune response - the first-line, non-specific strand of the immune system. Human macrophages were hyperresponsive, as were both macrophages and microglia (the brain's immune cells) from Huntington's disease model mice. This hyperresponsiveness reflected huntingtin's effect within cells, rather than a response to external signals.
Recently, Professor Tabrizi's group has extended these findings significantly. Immune cells from Huntington's disease patients were found to be releasing high levels of a range of cytokines involved in innate immune responses. These responses were due at least in part to the action of mutant huntingtin on the well-characterised NF-κB intracellular signalling pathway.
Furthermore, using a novel gene-silencing technique - huntingtintargeting small interfering RNA encased in polysaccharide shells that are readily taken up by phagocytic cells - the group was able to lower huntingtin levels and normalise cytokine production.
Persistently high cytokine levels could underlie a range of health problems in Huntington's disease, such as weight loss and depression. RNA-based methods targeting huntingtin in immune cells could be a viable strategy for ameliorating these effects. Moreover, as evidence is accumulating that immune responses influence disease progression in the brain, the findings also identify the NF-κB pathway as a possible target for interventions that have an impact on neurodegeneration.