Calcium Dyshomeostasis and Lysosomal Ca2+ Dysfunction in Amyotrophic Lateral Sclerosis (original) (raw)
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Calcium dysregulation in amyotrophic lateral sclerosis
Cell Calcium, 2010
In the fatal neurodegenerative disease amyotrophic lateral sclerosis (ALS), motor neurons degenerate with signs of organelle fragmentation, free radical damage, mitochondrial Ca 2+ overload, impaired axonal transport and accumulation of proteins in intracellular inclusion bodies. Subgroups of motor neurons of the brainstem and the spinal cord expressing low amounts of Ca 2+ buffering proteins are particularly vulnerable. In ALS, chronic excitotoxicity mediated by Ca 2+ -permeable AMPA type glutamate receptors seems to initiate a self-perpetuating process of intracellular Ca 2+ dysregulation with consecutive endoplasmic reticulum Ca 2+ depletion and mitochondrial Ca 2+ overload. The only known effective treatment, riluzole, seems to reduce glutamatergic input. This review introduces the hypothesis of a "toxic shift of Ca 2+ " within the endoplasmic reticulum-mitochondria Ca 2+ cycle (ERMCC) as a key mechanism in motor neuron degeneration, and discusses molecular targets which may be of interest for future ERMCC modulating neuroprotective therapies.
Deviant lysosomal Ca(2+) signalling in neurodegeneration. An introduction
Messenger (Los Angeles, Calif. : Print), 2016
Lysosomes are key acidic Ca(2+) stores. The principle Ca(2+)-permeable channels of the lysosome are TRP mucolipins (TRPMLs) and NAADP-regulated two-pore channels (TPCs). Recent studies, reviewed in this collection, have linked numerous neurodegenerative diseases to both gain and loss of function of TRPMLs/TPCs, as well as to defects in acidic Ca(2+) store content. These diseases span rare lysosomal storage disorders such as Mucolipidosis Type IV and Niemann-Pick disease, type C, through to more common ones such as Alzheimer and Parkinson disease. Cellular phenotypes, underpinned by endo-lysosomal trafficking defects, are reversed by chemical or molecular targeting of TRPMLs and TPCs. Lysosomal Ca(2+) channels therefore emerge as potential druggable targets in combatting neurodegeneration.
Frontiers in cellular neuroscience, 2014
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 serve as a promising targets for therapeutic approaches for treatment of ALS.
Scientific Reports
The aetiology of Amyotrophic Lateral Sclerosis (ALS) is still poorly understood. The discovery of genetic forms of ALS pointed out the mechanisms underlying this pathology, but also showed how complex these mechanisms are. Excitotoxicity is strongly suspected to play a role in ALS pathogenesis. Excitotoxicity is defined as neuron damage due to excessive intake of calcium ions (Ca2+) by the cell. This study aims to find a relationship between the proteins coded by the most relevant genes associated with ALS and intracellular Ca2+ accumulation. In detail, the profile of eight proteins (TDP-43, C9orf72, p62/sequestosome-1, matrin-3, VCP, FUS, SOD1 and profilin-1), was analysed in three different cell types induced to raise their cytoplasmic amount of Ca2+. Intracellular Ca2+ accumulation causes a decrease in the levels of TDP-43, C9orf72, matrin3, VCP, FUS, SOD1 and profilin-1 and an increase in those of p62/sequestosome-1. These events are associated with the proteolytic action of two...
Ca2+, mitochondria and selective motoneuron vulnerability: implications for ALS
Trends in Neurosciences, 2005
Motoneurons are selectively damaged in amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder. Although the underlying mechanisms are not completely understood, increasing evidence indicates that motoneurons are particularly sensitive to disruption of mitochondria and Ca 2C -dependent signalling cascades. Comparison of ALS-vulnerable and ALS-resistant neurons identified low Ca 2C -buffering capacity and a strong impact of mitochondrial signal cascades as important risk factors. Under physiological conditions, weak Ca 2C buffers are valuable because they facilitate rapid relaxation times of Ca 2C transients in motoneurons during high-frequency rhythmic activity. However, under pathological conditions, weak Ca 2C buffers are potentially dangerous because they accelerate a vicious circle of mitochondrial disruption, Ca 2C disregulation and excitotoxic cell damage.
Contents 3.1.7 Impact of plasma membrane depolarisation on mitochondrial Ca 2+ uptake and [Ca 2+ ]i release in brain stem slices of juvenile and adult WT and S0D1 G93A mice…………….…..………………………………....…....59 3.1.8 Pharmacological manipulation of ER in motoneurons by cyclopiazonic acid (CPA) inhibition of SERCA and its impact on differential Ca 2+ store regulation………………………………………………………….61 3.1.9 Interaction between ER and mitochondria in differential Ca 2+ store regulation and the role of ER as a Ca 2+ sequestering organelle in juvenile and adult brain stem slices of WT and S0D1 G93A mice…………………….…..63 3.2 Role of Mitochondria in SH-SY5Y Cells in defining Ca 2+ Metabolism of ALS Vulnerable Motoneurons ………………………………………….….….…66 3.2.1 Impaired ability of SH-SY5Y Neuroblastoma cells transfected with SOD1 G93A to cope with FCCP-induced Ca 2+ influx…………………….……..66 3.2.2 Effect of High K +-evoked Ca 2+ transient and its impact on FCCP-induced Ca 2+ influx in WT and SOD1 G93A transfected SH-SY5Y neuroblastoma cells....67 3.3 Simultaneous Measurement of Cytosolic and Mitochondrial Ca 2+ Concentrations in WT-SOD1 and SOD1 G93A transfected SH-SY5Y Neurobalstoma Cells Culture Model of Motoneuron Disease…………….……..70 3.3.1 Monitoring cytosolic (Fura-2) and mitochondrial (Rhod-2) Ca 2+ concentration with a temporal resolution in the millisecond time domain after inhibition of mitochondrial Ca 2+ sequestration in WT-SOD1 and SOD1 G93A transfected SH-SY5Y cells ……..………………………………………………….…….…71 3.3.2 Involvement of ER and mitochondria in shaping [Ca 2+ ]i and [Ca 2+ ]m regulation in WT-SOD1 and SOD1 G93A transfected SH-SY5Y cells…………...73 3.4 Study of Calcium Buffering Capacity and its Impact on Motoneurons……...…76 3.4.1 Calbindin-D 28k decreases [Ca 2+ ]i following stimulations in motoneurons…....76 3.4.2 Calbindin-D 28k decreases the susceptibility of motoneurons to excitability and increases the decay time constant (Ca 2+ clearance rates (τ)….….….…..78 3.5 Validation of Riluzole and Melatonin as a Neuroprotective Drug by Inhibition of Ca 2+ Signaling in HMNs of WT and SOD1 G93A Mice ………...……….….…..80 3.5.1 Riluzole mediate mild and reversible but delayed blockade of the [Ca 2+ ]i in fura-2/AM loaded HMNs exposed to Na +-azide in 14-15 weeks old symptomatic SOD1 G93A transgenic mice……………………………..…..…....80 iii Contents 3.5.2 Melatonin fails to block [Ca 2+ ]i signaling through Na +-channels in fura-2/AM loaded HMNs in WT and symptomatic SOD1 G93A mice ……….….83 3.6 Dynamic Calcium Signaling between Neuron-Glia and its implications in Physiology and Pathophysiology………………………………………….…....86
Antioxidants, 2022
Calcium (Ca2+) is a versatile secondary messenger involved in the regulation of a plethora of different signaling pathways for cell maintenance. Specifically, intracellular Ca2+ homeostasis is mainly regulated by the endoplasmic reticulum and the mitochondria, whose Ca2+ exchange is mediated by appositions, termed endoplasmic reticulum–mitochondria-associated membranes (MAMs), formed by proteins resident in both compartments. These tethers are essential to manage the mitochondrial Ca2+ influx that regulates the mitochondrial function of bioenergetics, mitochondrial dynamics, cell death, and oxidative stress. However, alterations of these pathways lead to the development of multiple human diseases, including neurological disorders, such as amyotrophic lateral sclerosis, Friedreich’s ataxia, and Charcot–Marie–Tooth. A common hallmark in these disorders is mitochondrial dysfunction, associated with abnormal mitochondrial Ca2+ handling that contributes to neurodegeneration. In this work...
Mitochondrial Ca2+ and neurodegeneration
Cell Calcium, 2012
Mitochondria are essential for ensuring numerous fundamental physiological processes such as cellular energy, redox balance, modulation of Ca 2+ signaling and important biosynthetic pathways. They also govern the cell fate by participating in the apoptosis pathway. The mitochondrial shape, volume, number and distribution within the cells are strictly controlled. The regulation of these parameters has an impact on mitochondrial function, especially in the central nervous system, where trafficking of mitochondria is critical to their strategic intracellular distribution, presumably according to local energy demands. Thus, the maintenance of a healthy mitochondrial population is essential to avoid the impairment of the processes they regulate: for this purpose, cells have developed mechanisms involving a complex system of quality control to remove damaged mitochondria, or to renew them. Defects of these processes impair mitochondrial function and lead to disordered cell function, i.e., to a disease condition. Given the standard role of mitochondria in all cells, it might be expected that their dysfunction would give rise to similar defects in all tissues. However, damaged mitochondrial function has pleiotropic effects in multicellular organisms, resulting in diverse pathological conditions, ranging from cardiac and brain ischemia, to skeletal muscle myopathies to neurodegenerative diseases. In this review, we will focus on the relationship between mitochondrial (and cellular) derangements and Ca 2+ dysregulation in neurodegenerative diseases, emphasizing the evidence obtained in genetic models. Common patterns, that recognize the derangement of Ca 2+ and energy control as a causative factor, have been identified: advances in the understanding of the molecular regulation of Ca 2+ homeostasis, and on the ways in which it could become perturbed in neurological disorders, may lead to the development of therapeutic strategies that modulate neuronal Ca 2+ signaling.
Journal of Neuroscience, 2013
Mitochondria have been proposed as targets for toxicity in amyotrophic lateral sclerosis (ALS), a progressive, fatal adult-onset neurodegenerative disorder characterized by the selective loss of motor neurons. A decrease in the capacity of spinal cord mitochondria to buffer calcium (Ca 2ϩ) has been observed in mice expressing ALS-linked mutants of SOD1 that develop motor neuron disease with many of the key pathological hallmarks seen in ALS patients. In mice expressing three different ALS-causing SOD1 mutants, we now test the contribution of the loss of mitochondrial Ca 2ϩ-buffering capacity to disease mechanism(s) by eliminating ubiquitous expression of cyclophilin D, a critical regulator of Ca 2ϩ-mediated opening of the mitochondrial permeability transition pore that determines mitochondrial Ca 2ϩ content. A chronic increase in mitochondrial buffering of Ca 2ϩ in the absence of cyclophilin D was maintained throughout disease course and was associated with improved mitochondrial ATP synthesis, reduced mitochondrial swelling, and retention of normal morphology. This was accompanied by an attenuation of glial activation, reduction in levels of misfolded SOD1 aggregates in the spinal cord, and a significant suppression of motor neuron death throughout disease. Despite this, muscle denervation, motor axon degeneration, and disease progression and survival were unaffected, thereby eliminating mutant SOD1-mediated loss of mitochondrial Ca 2ϩ buffering capacity, altered mitochondrial morphology, motor neuron death, and misfolded SOD1 aggregates, as primary contributors to disease mechanism for fatal paralysis in these models of familial ALS.