New mechanism in Amyotrophic lateral sclerosis (ALS)

Research Published October 26 2016
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Amyotrophic lateral sclerosis (ALS) is a rare fatal neurodegenerative disease, with rapid progression. There is currently no treatment for this disease.

Among the different mutations that can be responsible for the ALS, a mutation on a specific gene (C9ORF72) has already been identified as implicated in ALS, but the gene function is still unknown. Edor Kabashi’s team, in collaboration with Nicolas Charlet-Berguerand’s team at the IGBMC (CNRS, Inserm, University of Strasbourg), looked at the function of the gene and highlighted a new mechanism in the development of ALS. These results, published in EMBO journal followed by a News and Views in the same journal and a commentary in AUTOPHAGY journal, open the way to new therapeutic strategies.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with quick progression. It targets motor neurons, neurons that go from the brain and spinal cord to control muscles. Patients diagnosed with ALS suffer from progressive motor disability leading to paralysis. In France, ALS affects over 8 000 patients. To date, there is no treatment for this disease.

Familial ALS (fALS) represent 5% to 10% of the cases for 90% to 95% of sporadic ALS that is to say with no family history (sALS). Previous studies showed that a mutation on C9ORF72 gene could be responsible for 20% to 50% of fALS and 5% to 20% of sALS. However, despite the importance of this gene, its function is, to this day, still unknown.

Scientists from Edor Kabashi’s team, in collaboration with Nicolas Charlet-Berguerand’s team at the IGBMC, looked at the function of this gene. They showed that decreased expression of C9ORF72 gene had an impact on macroautophagy, a mechanism that makes possible the elimination of dysfunctional proteins, which accumulate in the brain and form toxic aggregates. This mechanism is essential to the proper functioning of the brain.

Maria-Letizia Campanari and Sorana Ciura, postdoctoral researchers in Edor Kabashi’s team also showed that a decrease in the expression of C9ORF72 gene leads to the formation of Ataxin2 protein aggregates, rendering them toxic. The sole decrease of C9ORF72 expression do not lead to neuron degeneration, just as Ataxin2 is not toxic on its own. It is the combination of C9ORF72 gene decreased expression and Ataxin2 expression that leads to cell death. These results suggest a mechanism of damage accumulation or sensitization to certain factors, in ALS.

Overall, the results of this study should allow to better understand the molecular causes of ALS to establish future therapeutic strategies.


References :
Loss of C9ORF72 impairs autophagy and synergizes with polyQ Ataxin-2 to induce motor neuron dysfunction and cell death. Sellier C, Campanari ML, Julie Corbier C, Gaucherot A, Kolb-Cheynel I, Oulad-Abdelghani M, Ruffenach F, Page A, Ciura S, Kabashi E, Charlet-Berguerand N. EMBO J. 2016 Jun.
The most prevalent genetic cause of ALS-FTD, C9orf72 synergizes the toxicity of ATXN2 intermediate polyglutamine repeats through the autophagy pathway. Ciura S, Sellier C, Campanari ML, Charlet-Berguerand N, Kabashi E. Autophagy. 2016 Aug.