RT Journal Article
SR Electronic
T1 Reduced Calreticulin Levels Link Endoplasmic Reticulum Stress and Fas-Triggered Cell Death in Motoneurons Vulnerable to ALS
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 4901
OP 4912
DO 10.1523/JNEUROSCI.5431-11.2012
VO 32
IS 14
A1 Nathalie Bernard-Marissal
A1 Anice Moumen
A1 Claire Sunyach
A1 Christophe Pellegrino
A1 Keith Dudley
A1 Christopher E. Henderson
A1 Cédric Raoul
A1 Brigitte Pettmann
YR 2012
UL http://www.jneurosci.org/content/32/14/4901.abstract
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.