Research Topic

The role of mitochondria, oxidative stress and altered calcium homeostasis in Amyotrophic Lateral Sclerosis: from current developments in the laboratory to clinical treatments.

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Selective vulnerability of motor neurons (MNs) in Amyotrophic Lateral Sclerosis (ALS) and associated mouse models is closely linked to exceptional Ca2+ signaling mechanisms that are part of the physiological cell function, but also enhance the risk of Ca2+ homeostasis disruption and mitochondrial dysfunction ...

Selective vulnerability of motor neurons (MNs) in Amyotrophic Lateral Sclerosis (ALS) and associated mouse models is closely linked to exceptional Ca2+ signaling mechanisms that are part of the physiological cell function, but also enhance the risk of Ca2+ homeostasis disruption and mitochondrial dysfunction in vulnerable cells. Despite extensive research since ALS was first described by Charcot more than 130 years ago, the molecular abnormalities which lead to damage of specific MNs in ALS have yet to be identified. Early studies suggest that uncontrolled Ca2+ entry and inefficiencies to sequester this calcium is causes selective damage leading to the formation of vacuoles derived from the degenerating mitochondria in the MNs of the mouse model of ALS. In contrast to most other neurons, MNs have a low Ca2+-buffering capacity due to the low expression of Ca2+-buffering proteins and a high number of Ca2+-permeable AMPA receptors resulting from a low expression of the GluR2 subunit. The combination of these two properties seems to be intrinsic to MNs and is most likely essential for their normal function. However, under pathological conditions, MNs could become over stimulated by glutamate and overwhelmed by Ca2+, although whether downstream pathways activated by the intracellular Ca2+ increase are different in MNs compared to other neurons is not yet known.
It is hypothesized that disrupted Ca2+ homeostasis and oxidative stress induced by reactive oxygen species have a vital role in propagating injury by increasing the excitability of MNs and by targeting neighboring glia. Excitotoxicity results most likely due to increased activity-dependent Ca2+ influx and associated mitochondrial Ca2+ cycling. Given the mitochondrial disturbances, Ca2+ buffering becomes inefficient and cytosolic Ca2+ levels rise. One protective option is to increase the resistance of MNs to high intracellular Ca2+ concentrations by inducing defense mechanisms and/or inhibiting the downstream pathways activated by increased intracellular Ca2+ concentrations. However, severely impaired MNs are forbidden from taking functional advantage for neuronal protection in ALS. These include a more defined separation of spatial Ca2+ gradient signal cascades. In conclusion, it seems that ALS is a multifactorial disease where under physiological conditions diffusion-restricted and tightly controlled domains might indeed have several functional advantages. Accordingly, therapeutic measures aimed at protecting mitochondrial function could be useful in various forms of ALS. Therefore, a combined pharmacological interference with the many faces of excitotoxicity both in MNs and surrounding glial cells will most likely be essential to extending the survival of ALS patients. However, it is clear that more structural and functional studies are still needed to identify potential cytosolic pathways and barriers that could lead to MN degeneration in ALS.
In this Research Topic, our emphasis is on outlining progress made in understanding the basic mechanistic role of mitochondria, excitotoxicity and altered calcium homeostasis in selective MN degeneration. We welcome investigators to contribute original research articles, perspectives, as well as review articles or case reports that will stimulate the continuing efforts to understand the mechanism underlying causes of this neurodegenerative disease.


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