Abstract
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of the motor system with complex determinants, including genetic and non-genetic factors. Despite this heterogeneity, a key pathological signature is the mislocalization and aggregation of specific proteins in the cytoplasm, suggesting that convergent pathogenic mechanisms focusing on disturbances in proteostasis are important in ALS. In addition, many cellular processes have been identified as potentially contributing to disease initiation and progression, such as defects in axonal transport, autophagy, nucleocytoplasmic transport, ER stress, calcium metabolism, the unfolded protein response and mitochondrial function. Here we review the evidence from in vitro and in vivo models of C9ORF72 and TDP-43-related ALS supporting a central role in pathogenesis for endoplasmic reticulum stress, which activates an unfolded protein response (UPR), and mitochondrial dysfunction. Disruption in the finely tuned signaling between the ER and mitochondria through calcium ions may be a crucial trigger of mitochondrial deficits and initiate an apoptotic signaling cascade, thus acting as a point of convergence for multiple upstream disturbances of cellular homeostasis and constituting a potentially important therapeutic target.
Highlights
Amyotrophic lateral sclerosis (ALS) is the most common type of motor neuron diseases and is characterized by progressive degeneration of upper and lower motor neurons, resulting in loss of voluntary muscle action and eventually death through respiratory failure
While the majority of early studies linking mitochondrial dysfunction with ALS were based on superoxide-dismutase 1 (SOD1) models, it has become evident in the last decade that both functional and morphological defects in mitochondria are found in other familial ALS cases, those due to mutations in TAR-DNA binding protein (TARDBP) or C9ORF72
We reported increased endoplasmic reticulum (ER) stress in iPSC-derived MNs from patients with C9ORF72 mutations, followed by reduced mitochondrial membrane potential and altered mitochondrial morphology (Dafinca et al, 2016)
Summary
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of the motor system with complex determinants, including genetic and non-genetic factors. Despite this heterogeneity, a key pathological signature is the mislocalization and aggregation of specific proteins in the cytoplasm, suggesting that convergent pathogenic mechanisms focusing on disturbances in proteostasis are important in ALS. Many cellular processes have been identified as potentially contributing to disease initiation and progression, such as defects in axonal transport, autophagy, nucleocytoplasmic transport, ER stress, calcium metabolism, the unfolded protein response and mitochondrial function.
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