Huntington's disease is a rare neurodegenerative pathology. In France, it affects around 18,000 people, 12,000 of whom are not yet experiencing the classic symptoms of sudden involuntary movements and behavioral and cognitive disorders, which usually begin appearing between 30 and 50 years of age. Huntington's disease is caused by a mutation in the huntingtin gene, leading to a defective huntingtin protein, that in turn provokes neuronal degeneration in the striatum, a brain region associated with movement control. The exact mechanisms driving this neurodegeneration remain largely unknown. Avenues are being explored however, including that of an abnormality in transcription¹. A collaborative work² led by researchers at MIRCen has shed light on an enzyme, called DCLK3. The group showed that the presence of this enzyme in the striatum may be important for transcription regulation, and that its reduced expression in Huntington's disease may make neurodegeneration more likely.

The function of DCLK3 is currently unknown, but very recent studies suggest that it may modulate cell survival. In the collaborative work headed by Emmanuel Brouillet, director of the Neurodegenerative Diseases Laboratory at MIRCen, a murine model of Huntington's disease was used to show that the reduced expression of DCLK3 heightened the toxicity of mutant huntingtin protein. Inversely, increasing the expression of DCLK3 showed a neuroprotective effect. Also, in the murine model, reestablishing sufficient DCLK3 expression appeared to improve certain motor symptoms. In vitro experiments³ identified seven potential DCLK3 partner proteins. Surprisingly, all seven are known or presumed regulators of transcription. By determining gene expression levels in striatal cells as a function of DCLK3 activity, the researchers found that the enzyme likely acts in transcription regulation and chromatin remodeling⁴. Indeed, the team observed DCLK3 in the cell nucleus, where transcription takes place.

Considered globally, the results of this study, published in Brain, suggest a vicious circle: the effect of the mutant huntingtin protein on transcription would be initially limited, but because that effect reverberates on DCLK3, transcription deregulation would progressively increase. Thus, in the future, modulating DCLK3 activity could become a new treatment strategy for Huntington's disease, and possibly for other neurodegenerative disorders as well.

¹ Transcription is the transfer of genetic information from DNA to RNA; it is the first step on the protein production pathway.

² With teams from the Grenoble Neurosciences Institute, the Integrative Biology of the Cell group (I2BC) of the Frédéric-Joliot Institute (CEA Paris-Saclay), I-STEM in Évry, the Laboratory of Adaptive and Cognitive Neurosciences (LNCA) in Strasbourg and Lausanne University (Switzerland).

³ By yeast two-hybrid screening.

⁴ Located in the nucleus, chromatin comprises the cell's DNA in interaction with other proteins, notably those necessary for DNA compaction. In differentiated cells, including neurons, chromatin is constantly "remodeled" by epigenetic mechanisms (modifying gene function without changing the DNA sequence) that precisely control gene transcription.