​Huntington's disease is a rare, hereditary, currently uncurable and ultimately fatal neurodegenerative disease. Its symptoms include serious motor, cognitive and psychiatric disorders.

The disease is caused by a mutation in the huntingtin gene. The resulting muted protein is not only unable to carry out its normal functions, it also becomes toxic for neurons, provoking the activation of cerebral defense mechanisms. A part of these latter is that the astrocytes, which normally play a support role for neurons, change their behavior, becoming "reactive."

Historically, reactive astrocytes have been considered as deleterious for the brain because they exacerbate the symptoms of other brain pathologies like Alzheimer's disease.

However, in a recent study published in the journal Brain, researchers from MIRCen's Neurodegenerative Diseases Laboratory (LMN), the National Center of Human Genomics Research (CNRGH) and GenoSplice technology used mouse models of Huntington's disease to show that stimulating reactive astrocyte formation favors the elimination of mutant huntingtin, reducing both the quantity and size of the aggregates.

The team used viral vectors in different murine models of Huntington's disease to specifically activate astrocyte reactivity via the JAK2-STAT3 signaling pathway. In so doing, the researchers showed that reactive astrocytes help neurons eliminate mutant huntingtin protein.

Furthermore, the mice showed improvements in certain molecular and functional characteristics of the disease, some of which are measurable noninvasively by MRI.

The cooperation between neurons and the astrocytes brought to the reactive state by JAK2-STAT3 activation comprised two complementary mechanisms:

• The reactive astrocytes gained in their ability to break down proteins by way of proteasomes (a complex of proteases whose role is to degrade misfolded or denatured proteins) and lysosomes, and were thus better able to degrade mutant huntingtin.
• The reactive astrocytes released exosomes containing chaperon proteins (DNAJB1/Hsp40) that the neurons used thereafter to eliminate mutant huntingtin.

Having made this demonstration of astrocyte-neuron cooperation in Huntington's disease, the researchers will now seek to identify the best methods for selectively stimulating reactive astrocytes, an objective they hope will open vistas on possible therapies.