Reduced Calreticulin Levels Link Endoplasmic Reticulum Stress and Fas-Triggered Cell Death in Motoneurons Vulnerable to ALS

Abstract

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 SOD1 G93A motoneuron death through the Fas/NO pathway. In SOD1 G93Amice 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 SOD1 G93A 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.

Lifeguard Inhibits Fas Ligand-mediated Endoplasmic Reticulum-Calcium Release Mandatory for Apoptosis in Type II Apoptotic Cells

“…It interacts with Bcl-X L in the ER and regulates calcium signaling (29). Fas-mediated apoptosis shares some features with intrinsic death pathways, such as ER stress (43,44), and promotes a rise in intracellular calcium (45,46), which mediates some apoptotic features attributed to FasL-induced cell death (35). The cross-talk between the ER and mitochondria and the calcium efflux between them are important steps in Fas apoptotic signaling, at least in the immune system (47).…”

Marinesco-Sjögren syndrome protein SIL1 regulates motor neuron subtype-selective ER stress in ALS

“…7c). We examined the expression of Derlin-1 and CRT, as impaired ER homeostasis due to their functional alterations in mutant SOD1 models has been reported 27,28 . Derlin-1 and CRT expression was enhanced in AAV6-SIL1-transduced motor neurons as compared to untransduced motor neurons ( Fig.…”

Calcium-dependent protein folding in amyotrophic lateral sclerosis

“…The authors offer several possible reasons for these findings. For instance, a change in Ca 2+ homoeostasis can influence the expression of calreticulin [6,89] or that mutated SOD1 can directly aggregate with calreticulin [90,91]. Recently, BernardMarissal et al demonstrated that expression of calreticulin is linked with the Fas/NO pathway and motor neuron death [91].…”