Endoplasmic reticulum stress and the ER mitochondria calcium cycle in amyotrophic lateral sclerosis

Abstract

The endoplasmic reticulum (ER) is a multifunctional organelle involved in protein synthesis, processing and folding, in intracellular transport and calcium signalling. ER stress can be triggered by depletion of ER calcium content and the accumulation of un- and mis-folded proteins, and relays stress signals to the ER mitochondria calcium cycle (ERMCC) and to the nucleus and protein translation machinery. The ensuing unfolded protein response (UPR) helps to cope with ER stress. Total protein synthesis is inhibited to keep protein load low, while the synthesis of ER chaperones, which assist protein folding, is induced. If cell integrity cannot be restored, signal cascades mediating cell death are activated. This review focuses on the role of ER stress and the UPR in the pathology of amyotrophic lateral sclerosis (ALS). The triggers for ER stress are as yet unclear, but induction of UPR sensor proteins, up-regulation of chaperones and induction of cell death proteins have been described in human post mortem ALS tissue and in mutant superoxide dismutase-1 (SOD1) expressing models of ALS. TDP-43 and VAPB seem to be involved in UPR signalling as well. Recent reports raise hope that UPR sensor proteins become effective therapeutic targets in the treatment of ALS.

Calcium-dependent protein folding in amyotrophic lateral sclerosis

“…Recent studies indicate that ER stress is involved in the pathogenesis of both familial and sALS [3]. Western blott analysis of spinal cords from a mutated SOD1 transgenic mice model and from ALS patients showed upregulation of all three UPR sensors IRE1, ATF6, and PERK [47,48].…”

“…In addition, a hexanucleotide (GGGGCC) repeat expansion in the first intron of the C9ORF72 gene [1,2] has also lately been demonstrated as being associated with ALS. However, the etiology of the disease is still unclear, although recent studies indicate that Ca 2+ disturbances, endoplasmic reticulum (ER) stress, and mitochondrial dysfunction are involved in the pathogenesis of ALS [3,4]. The ER is a continuous network of membranes housing many functions critical to cellular survival [5].…”

Myasthenia gravis and amyotrophic lateral sclerosis: A pathogenic overlap

“…The molecular pathogenesis of ALS is not well understood, resulting in a lack of appropriate target and mechanism-based therapies. Various hypotheses have been put forward, including gene defects [11], alterations in RNA metabolism [12], mitochondrial dysfunction [13], protein aggregation defects [14], glutamate excitotoxicity [15], and autoimmune mechanisms [16][17][18]. Such molecular mechanisms may be parallel alterations that account for selective vulnerability of motor neurons rather than causative events.…”

Protective effect of valproic acid on cultured motor neurons under glutamate excitotoxic conditions. Ultrastructural study

“…Dysfunction of neuronal mitochondria has been suggested to play an important role in MN degeneration [20]. The oxidative and endoplasmic reticulum (ER) stress [16,17] and deregulation of the ER mitochondrial calcium cycle [22] are described as the most likely causes of motor neuronal death, but it is believed that a complex mechanism of multiple toxic pathways is implicated in the ALS onset and progression [32]. Glutamate-induced excitotoxicity is also considered as one of the possible pathophysiological factors of motor neuron death [4,12].…”