A recent study indicates that removing the immune cytokine IL-6 worsens symptoms in HD model animals and alters brain connectivity genes.
“If one looks back in the Huntington’s disease field literature, many people have postulated that IL-6 reductions would be therapeutic in HD,” said Myriam Heiman, an associate professor in MIT’s Department of Brain and Cognitive Sciences and a member of The Picower Institute for Learning and Memory and the Broad Institute of MIT and Harvard. She is the paper’s senior author in Molecular Neurodegeneration. Mary Wertz, a former postdoc, is the primary author.
The researchers crossedbred animals made to represent HD with mice created to lack IL-6 to test the idea that cutting off IL-6 might assist HD mice. They then compared progeny performance on a range of typical mobility tests to that of healthy mice, animals without IL-6, and mice modelling HD but still possessing IL-6. The HD mice missing IL-6 outperformed all other mouse lines, including the HD mice that still possessed IL-6.
The finding was surprising not only because of the track record in previous studies, but also because Wertz and Heiman conducted a broad analysis of genes that promoted neuron survival in Huntington’s disease earlier this year, and some of the hits they discovered were associated with interleukin signalling.
The team was astounded by the new study’s findings and tried to understand why they occurred. To do so, scientists sequenced RNA from hundreds of individual cells in each mouse strain and assessed gene expression in all of the major cell types in the striatum, the brain area most affected by HD.
When they compared the differences in gene expression in neurons between the two HD mouse lines, those with IL-6 and those without, they discovered that many genes important for synapses, the connections that connect neurons into circuits, were significantly less expressed in the HD mice without IL-6.
“Perhaps this deterioration of the phenotypic is related to disruption of those synaptic signalling pathways,” Heiman speculated.
While the study found no therapeutic effect to totally eliminating IL-6, Heiman believes it is still feasible to discover a therapeutic equilibrium between overexpression and complete elimination. It is also likely that time is critical.
For example, in this study, mice lacked IL-6 from birth, but she believes that acting to modify IL-6 levels may be more useful later in life. The lab intends to explore the inquiry further.
“What these findings demonstrate is that we really need to understand which aspects of innate immune signalling are triggered when and in what order,” she added.
