Researchers have discovered the way in which the generation of the gene at the origin of Huntington’s disease kills striatal neurons, opening the way to potential new treatments.
- The mutation of the Huntingtine gene (HTT) becomes toxic when CAG rehearsals exceed 150.
- This expansion of rehearsals slowly kills striatal neurons, which play a role in various functions (cognition, motor and behavioral).
- The researchers hope that this study will allow the development of new therapies to slow down and prevent disease.
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 carrying the hereditary mutation of the Huntingtine gene (HTT). It is this mutation which is at the origin of the disease because it causes the death of the brain cells.
Huntington’s disease impacts striatal neurons from 150 CAG
“”Usually this gene [HTT] Includes a sequence made up of 35 repetitions of a triplet of nucleotides (CAG), which codes for amino glutamine acid, Can we read on the Inserm website. But in Huntington’s disease, there is an anomaly in the number of repetitions of this triplet. Schematically, the greater the number of repetitions, the earlier the start of the disease. “
So far, scientists have not known how this mutation resulted in the death of brain cells. But, a new study, published in the journal Cellprovides the answer. Indeed, the researchers discovered the mechanism by which this hereditary genetic mutation led to the death of the brain cells.
For this, they analyzed the cerebral tissues of 53 people with Huntington’s disease and 50 others who were not reached. 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 CAG (while most previous research on the human brain fabric focused on sequences of less than 100 CAG).
– Go from 40 to 150 CAG had no impact on the health of these neurons.
– Beyond 150 CAG, these neurons were impacted, distorted and ended up dying.
For those affected, scientists therefore discovered the following mechanism: it takes several decades to reach 80 CAG. Then, the expansion rate accelerates rapidly (a few years) until reaching 150 CAG. From this threshold, striatal neurons die. This means that, for 95 % of the life of striatal neurons, the mutation of the HTT gene is harmless. It is slowly transformed 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 start this work, but there were shortcomings and inconsistencies in our collective understanding, indicates Bob Handsaker, one of the authors, in a press release. We were able to reconstruct the complete path of pathology over the decades in neurons, which potentially gives us many different moments when 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 down or stop the increase in CAGs.
