Calcium-dependent protein folding in amyotrophic lateral sclerosis

Mitochondrial Ca2+ in neurodegenerative disorders

“…Mitochondrial Ca 2+ overload and mPTP opening are two of the major players in cell death. Mutation in SOD1 also changes the ER -mitochondria intercommunications -and decreases the level of Ca 2+ -binding protein cytosol, leading to mitochondrial calcium overload and dysfunction [70,71].…”

Amyloidogenic lysozymes accumulate in the endoplasmic reticulum accompanied by the augmentation of ER stress signals

“…Although forced overexpression of the amyloidogenic mutant lysozymes leads to their rapid accumulation in the ER, it is estimated, in the case of human body, that the accumulation of the mutant proteins proceeds slowly, resulting in developing amyloidosis mainly in the 40-50's [5,45]. Several diseases including diabetes II [46] and amyotrophic lateral sclerosis (ALS) [47,48] are known to be brought about by the accumulation of misfolding proteins in the ER. A recent report indicated that, in Saccharomyces cerevisiae, unstable lysozymes may interact with a calnexin homolog, possibly causing their retention in the ER and subsequent elimination via ER-associated degradation [49].…”

Calcium dysregulation links ALS defective proteins and motor neuron selective vulnerability

“…In fact, major pathological processes in ALS involving excitotoxicity and the ER-mitochondria Ca 2+ cycle are deeply connected and potentially trigger or/and are enhanced by intracellular Ca 2+ deregulation: (a) Glutamatergic excitotoxicity is tough to be mediated by an excessive influx of extracellular ions, including Ca 2+ , resulting in elevated intracellular Ca 2+ levels that can activate cytoplasmatic Ca 2+ -dependent apoptotic proteins (e.g., calcineurin, calpain) which promote cell death (Wang et al, 1999; Kim et al, 2002); (b) elevated intracellular levels of Ca 2+ also lead to mitochondrial Ca 2+ overload, that is deeply interconnected with mitochondrial dysfunction resulting in ROS production, oxidative stress and eventually to apoptosis or necrosis (Kawamata and Manfredi, 2010; Cozzolino and Carrì, 2012); and (c) depletion of Ca 2+ levels in the ER which is suggested to occur via a persistent shift of Ca 2+ from the ER to the mitochondria due to deregulated ER MCC leads to protein folding dysfunction and proteasome impairment, resulting in ER stress and apoptosis (Prell et al, 2013; Tadic et al, 2014). Mutations in critical proteins associated with ALS actually seem to increase the susceptibility for these toxic processes to occur.…”