HUNTINGTON’S DISEASE: Repairing glia rather than neurons

Huntington’s disease, an inherited and fatal genetic disease, caused by the excess of a certain type of repeated RNA sequences in a gene – huntingtin – present in each cell, has long been considered a neuronal disease due to the permanent loss of motor neurons, whose death over time is responsible for the clinical signs of the disease: involuntary movements, coordination disorders, cognitive decline, depression and psychosis. However, a growing body of research, including this new study, suggests that the disease may also stem from defects in the brain’s supporting cells, glia.

“Huntington’s disease is a complex disease that affects both neurons and supporting cells. To use an analogy,

not only is the patient sick, but so are the doctor and the nurse,”

explains one of the main authors, Abdellatif Benraiss, associate professor of research in neurology.

With neurologist Steve Goldman from the University of Rochester, a leading specialist in Huntington’s disease, the team shows that 2 populations of glial cells present in the brain, astrocytes and oligodendrocytes, are dysfunctional in Huntington’s disease, and that this dysfunction can trigger much of the neuronal pathology observed. Indeed, glial cells play an essential role in maintaining the health of neurons and facilitate chemical signaling between nerve cells. In Huntington’s disease, glial cells are unable to perform these functions, which leads to a breakdown in communication between neurons and then, gradually, to cell death.

Loss of neurons and glial dysfunction: but while neuronal loss leads to symptoms and death, “reversing” glial dysfunction early in the course of the disease could help preserve neuron health and thus prevent disease progression.

The study indeed focuses on oligodendrocytes and identifies how the deletion of a specific transcription gene called Tcf7l2 triggers a series of changes that impair the function of oligodendrocyte progenitor cells (OPCs). These cells constantly replenish the brain with oligodendrocytes, which in turn “refresh” the myelin insulation that helps signals travel faster through the brain. However, in Huntington’s disease, the OPCs are not or no longer able to meet the demand, which leads to deficient myelination in the brain or atrophy of the white matter.

  • However, the overexpression of Tcf7l2 in Huntington’s model mice, ie carriers of the disease mutation, allows a renewal of OPC function and a restoration of myelin.

These new data confirm the conclusions of previous studies which highlighted the dysfunction of astrocytes – the other glial population – which support neurons and their synaptic connections.

Taken together, these results provide a better understanding of the mechanisms that, in Huntington’s disease, impair glial cell function and ultimately lead to neurological disability. Finally, glial cells are designated as new cellular and molecular targets for new therapies that will consist of repairing supporting cells, before replacing lost neurons.

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