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Scientific news

Discovery of a new pathogenic mechanism in Amyotrophic lateral sclerosis

The loss of C9ORF72 partially alters macroautophagy but doesn’t cause neuronal cell death. In contrast, decreasing expression of C9ORF72 increases the aggregation and toxicity of Ataxin-2 containing polyglutamine repeats. The number of polyglutamine in ATXN2 gene is a genetic modifier known in ALS.

Loss of C9ORF72 impairs autophagy and synergizes with polyQ Ataxin-2 to induce motor neuron dysfunction and cell death.

Sellier C(1), Campanari ML(2), Julie Corbier C(3), Gaucherot A(3), Kolb-Cheynel I(3), Oulad-Abdelghani M(3), Ruffenach F(3), Page A(3), Ciura S(2), Kabashi E(2), Charlet-Berguerand N(1).

EMBO J April 21, 2016

April 21, 2016

The team of Nicolas Charlet-Berguerand at the IGBMC in collaboration with the team of Edor Kabashi at the Institute for Brain and Spinal Cord Disorders (ICM) in Paris have set light a new pathogenic mechanism in Amyotrophic lateral sclerosis. These results were published in the journal EMBO, April 21th 2016.

Amyotrophic lateral sclerosis (ALS), is a neurodegenerative disease which has a rapidly developing. It attacks the motor neurons directly, nerve cells which serve as control units and communication links between the nervous system and the voluntary muscles of the body until total atrophy of all muscles. Actually, there is no treatment against this disease.


The majority of ALS cases are sporadic (sALS) but 5-10% of cases have a familial transmission (fALS). In previous studies, it has been shown that the most frequent mutation resulted from a GGGGCC repeat expansion in the non-coding first portion of the C9ORF72 gene. This mutation could be responsible for 20-50% of fALS and 5 to 20% of sALS. However, despite the importance of C9ORF72 gene, its function is actually unknown.


The decreased expression of the gene C9ORF72 alters the Macroautophagy

This collaborative study was conducted with the team of Edor Kabashi at the ICM and funded by the French Association against Myopathies (FMA), the European Research Council (ERC), the Foundation of Thierry Latran, Inserm and Labex-NRTIs (ANR). As part of this work, the team of Nicolas Charlet-Berguerand provided a molecular and cellular function to the C9ORF72 gene as protein regulating initiation of macro autophagy. Autophagy is a cellular mechanism for "digestion" of molecules present in a part from the cytoplasm. This mechanism is essential to degrade molecules of large sizes such as dysfunctional protein aggregates. Consequently, macro autophagy is crucial for normal brain function.


The decreased expression of the gene C9ORF72 coordinates toxicity Ataxin2

Researchers have also shown that the decreased expression of C9ORF72 potentiates the aggregation and toxicity of Ataxin2 protein containing polyglutamine repeats. The Ataxin2 gene is known as a genetic modifier in the involvement of ALS but its pathogenesis remains obscure.


However, the sole decrease of C9ORF72 does not lead to degeneration of neurons. Similarly, Ataxin2 containing polyglutamine is not toxic alone. However, the combination of decreased C9ORF72 and expression Ataxin2 leads to cell death. Thus these results suggest damage accumulation mechanism or sensitization to certain stress in ALS.


The overall results of this study should provide a better understanding of the molecular root causes of ALS to determine future therapeutic strategies.

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