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Amyotrophic lateral sclerosis is characterized by progressive death of motor neurons (MNs) with glutamate excitotoxicity and mitochondrial Ca2+ overload as critical mechanisms in disease pathophysiology. We used MNs from G93AhSOD1 and nontransgenic embryonic cultures and adult mice to analyze the expression of the main mitochondrial calcium uniporter (MCU). MCU was overexpressed in cultured embryonic G93AhSOD1 MNs compared to nontransgenic MNs but downregulated in MNs from adult G93AhSOD1 mice. Furthermore, cultured embryonic G93AhSOD1 were rescued from kainate-induced excitotoxicity by the Ca2+/calmodulin-dependent protein kinase type II inhibitor; KN-62, which reduced MCU expression in G93AhSOD1 MNs. MCU activation via kaempferol neither altered MCU expression nor influenced MN survival. However, its acute application served as a fine tool to study spontaneous Ca2+ activity in cultured neurons which was significantly altered by the mutated hSOD1. Pharmacological manipulation of MCU expression might open new possibilities to fight excitotoxic damage in amyotrophic lateral sclerosis.

Mitochondria have long been implicated in Parkinson’s disease (PD), however, it is not clear how mitochondrial impairment and alpha-synuclein pathology are coupled. We report here that intra-mitochondrial protein homeostasis plays a major role in alpha-synuclein fibril elongation, as interference with intra-mitochondrial proteases and mitochondrial protein import significantly aggravate alpha-synuclein aggregation. In contrast, direct inhibition of mitochondrial complex I, increase in intracellular calcium concentration or formation of reactive oxygen species (ROS), all of which have been associated with mitochondrial stress, did not affect alpha-synuclein pathology. We further demonstrate that similar mechanisms are involved in Amyloid β 1-42 (Aβ42) aggregation, suggesting that mitochondria are directly capable of influencing cytosolic protein homeostasis of aggregation-prone proteins.

Amyotrophic lateral sclerosis is characterized by progressive death of motor neurons (MNs) with glutamate excitotoxicity and mitochondrial Ca

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.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive loss of upper and lower motor neurons. Although the etiology remains unclear, disturbances in calcium homoeostasis and protein folding are essential features of neurodegeneration in this disorder. Here, we review recent research findings on the interaction between endoplasmic reticulum (ER) and mitochondria, and its effect on calcium signaling and oxidative stress. We further provide insights into studies, providing evidence that structures of the ER mitochondria calcium cycle (ERMCC) serve as a promising targets for therapeutic approaches for treatment of ALS.