a new therapeutic approach to delay it?

In France, 18,000 people are affected by Huntington’s disease, according to the National Institute of Health and Medical Research (Inserm). Among them, 6,000 have symptoms, while the others are asymptomatic but carry the hereditary mutation of the huntingtin gene (HTT). It is this mutation which is at the origin of the disease because it causes the death of brain cells.

Huntington’s disease impacts striatal neurons from 150 CAG

“Usually this gene [HTT] comprises a sequence consisting of 35 repetitions of a triplet of nucleotides (CAG), which codes for the amino acid glutamine, can we read on the Inserm website. But in Huntington’s disease, we observe an anomaly in the number of repetitions of this triplet. Schematically, the greater the number of repetitions, the earlier the onset of the disease.”

Until now, scientists did not know how this mutation causes brain cells to die. But, a new study, published in the journal Cellprovides the answer. Indeed, researchers discovered the mechanism by which this hereditary genetic mutation led to the death of brain cells.

To do this, they analyzed the brain tissue of 53 people with Huntington’s disease and 50 others who did not have it. Thus, they made several observations and discoveries concerning striatal neurons, which play a role in various functions (cognition, motor and behavioral):

– Some of these neurons had up to 800 CAGs (while most previous research on human brain tissue focused on sequences of fewer than 100 CAGs

– Going from 40 to 150 CAG had no impact on the health of these neurons.

– Beyond 150 CAG, these neurons were impacted, deformed and ended up dying.

For affected people, scientists have therefore discovered the following mechanism: it takes several decades to reach 80 CAG. Then, the rate of expansion accelerates rapidly (a few years) until it reaches 150 CAG. From this threshold, striatal neurons die. This means that, for 95% of the life of striatal neurons, the HTT gene mutation is harmless. It slowly transforms into a highly toxic form which then quickly kills the cell.

Towards potential treatments to prevent this genetic disease

“We already knew a lot about Huntington’s disease before we began this work, but there were gaps and inconsistencies in our collective understanding, says Bob Handsaker, one of the authors, in a communiqué. We were able to reconstruct the full trajectory of pathology over decades in neurons, potentially giving us many different times where we can intervene therapeutically.”

Currently, Huntington’s disease remains an incurable pathology. But, thanks to this discovery, scientists hope to be able to develop new therapies. Indeed, instead of targeting the HTT gene, a new approach could be to slow or stop the increase in CAGs.