PT  - JOURNAL ARTICLE
AU  - Nathalie Bernard-Marissal
AU  - Anice Moumen
AU  - Claire Sunyach
AU  - Christophe Pellegrino
AU  - Keith Dudley
AU  - Christopher E. Henderson
AU  - Cédric Raoul
AU  - Brigitte Pettmann
TI  - Reduced Calreticulin Levels Link Endoplasmic Reticulum Stress and Fas-Triggered Cell Death in Motoneurons Vulnerable to ALS
AID  - 10.1523/JNEUROSCI.5431-11.2012
DP  - 2012 Apr 04
TA  - The Journal of Neuroscience
PG  - 4901--4912
VI  - 32
IP  - 14
4099  - http://www.jneurosci.org/content/32/14/4901.short
4100  - http://www.jneurosci.org/content/32/14/4901.full
SO  - J. Neurosci.2012 Apr 04; 32
AB  - Cellular responses to protein misfolding are thought to play key roles in triggering neurodegeneration. In the mutant superoxide dismutase (mSOD1) model of amyotrophic lateral sclerosis (ALS), subsets of motoneurons are selectively vulnerable to degeneration. Fast fatigable motoneurons selectively activate an endoplasmic reticulum (ER) stress response that drives their early degeneration while a subset of mSOD1 motoneurons show exacerbated sensitivity to activation of the motoneuron-specific Fas/NO pathway. However, the links between the two mechanisms and the molecular basis of their cellular specificity remained unclear. We show that Fas activation leads, specifically in mSOD1 motoneurons, to reductions in levels of calreticulin (CRT), a calcium-binding ER chaperone. Decreased expression of CRT is both necessary and sufficient to trigger SOD1G93A motoneuron death through the Fas/NO pathway. In SOD1G93A mice in vivo, reductions in CRT precede muscle denervation and are restricted to vulnerable motor pools. In vitro, both reduced CRT and Fas activation trigger an ER stress response that is restricted to, and required for death of, vulnerable SOD1G93A motoneurons. Our data reveal CRT as a critical link between a motoneuron-specific death pathway and the ER stress response and point to a role of CRT levels in modulating motoneuron vulnerability to ALS.