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A new pathogenic mechanism involved in Huntington’s disease

on the October 8, 2015

Cleavage of the huntingtin protein generates fragments affecting the functions of the endoplasmic reticulum


Huntington’s disease is a genetic disease affecting about 6,000 people in France and concerning more than 12,000 carriers of the mutant gene not yet showing any clinical signs. It is characterized by uncontrolled movements, a change in personality, dementia and death of the patients, ten to twenty years following the onset of the first symptoms.

The gene responsible for the disease, the HTT gene, synthesizes the huntingtin protein whose function is still unclear. In normal conditions, this protein contains repeats of the amino acid glutamine. These repeats can become harmful. Beyond a particular threshold (36 to 40 glutamines), the huntingtin becomes mutant and causes the disease, and the more repeats there are, the earlier the symptoms appear. It has been proved that this abnormal multiplication of glutamine is altering the huntingtin’s structure, thus leading to neuronal cell death.

In order to develop new therapeutic strategies, the priority is to understand the cellular mechanisms through which the mutant huntingtin causes neuronal cell death in patients affected by Huntington’s disease.

A number of these mechanisms are already known. The huntingtin's cleavage and the formation of a fragment containing the repeat of glutamines constitute a major phase, and for many laboratories, it has been a priority to study this fragment as it contains the glutamine repeat. These studies have demonstrated its toxic effect in the nucleus as it inhibits transcription. However, until now, few studies focused on the consequences of the protein cleavage. With the creation of an artificial system that could be used for real-time control of this cleavage, the researchers of the “Intracellular Dynamics and Neurodegeneration” team led by Frédéric Saudou have demonstrated that cleavage of the huntingtin causes an alteration in the functioning of the endoplasmic reticulum due to the formation of this second fragment whose role has yet to be thoroughly studied.

These studies contribute to a better understanding as to how the mutant huntingtin causes cell death through a twin toxic mechanism. The results should lead to the development of more appropriate therapeutic strategies taking into account this twin mechanism.


In these cultured cells, cleavage of the huntingtin leads to the formation of vacuoles resulting from an endoplasmic reticulum an abnormal fusion of the endoplasmic reticulum. These vacuoles are positive for the huntingtin (left panel and in green) and for the calnexin, a specific marker of the endoplasmic reticulum (middle panel and in red). The nuclei are shown in blue. .

Référence :

El-Daher MT, Hangen E, Bruyère J, Poizat G, Al-Ramahi I, Pardo R, Bourg N, Souquere S, Mayet C, Pierron G, Lévêque-Fort S, Botas J, Humbert S, Saudou F. Huntingtin proteolysis releases non-polyQ fragments that cause toxicity through dynamin 1 dysregulation. EMBO J. 2015 Sep 2;34(17):2255-71. doi: 10.15252/embj.201490808. Epub 2015 Jul 12.


Updated on November 2, 2016

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