Respiratory function after selective respiratory motor neuron death from intrapleural CTB-saporin injections (original) (raw)
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Frontiers in cellular neuroscience, 2014
Amyotrophic lateral sclerosis (ALS), which was described since 1869 by Jean Martin Charcot, is a devastating neurodegenerative disease characterized by the selective and progressive loss of upper and lower motor neurons of the cerebral cortex, brainstem and the spinal cord. The result of this loss is a progressive and irreversible paralysis leading to a complete incapacity of movements and finally to respiratory failure, but the cognitive functions are not affected and is not merely the result of aging because may occur at young adult ages. There is still no treatment, prevention or reliable biomarkers of ALS and it is clear that this could only be accomplished, as for other neurodegenerative diseases, through the knowledge of the cellular and molecular pathophysiological mechanisms involved. Research on such mechanisms is, therefore, essential. Although progress in neurochemical, physiological, genetic and clinical investigations in the last decades has identified several cellular processes and mechanisms that seem to be involved in the neuronal death, such as glutamate receptors-mediated excitotoxicity, disruption of spinal inhibitory circuits, inflammatory events, axonal transport deficits, oxidative stress, mitochondrial dysfunction, energy failure, intracellular Ca 2+ dishomeostasis, protein aggregation and misfolding, changes in gene expression, astrocytes alterations, and non-cell autonomous toxic factors, the understanding of the origin and temporal progress of the disease is still incomplete and insufficient. Clearly, there is a need of further experimental models and approaches to discern the importance of such mechanisms and to discover the factors that determine the selective death of motor neurons characteristic of ALS, in contrast to other neurodegenerative diseases such as Parkinson's and Alzheimer's disease in which other neuronal types located in other CNS regions are predominantly affected.
Necroptosis is dispensable for motor neuron degeneration in a mouse model of ALS
Cell Death & Differentiation, 2019
Motor neuron degeneration in amyotrophic lateral sclerosis (ALS) is proposed to occur by necroptosis, an inflammatory form of regulated cell death. Prior studies implicated necroptosis in ALS based on accumulation of necroptotic markers in affected tissues of patients and mouse models, and amelioration of disease in mutant superoxide dismutase 1 (SOD1 G93A) mice with inhibition of the upstream necroptotic mediators, receptor interacting protein kinase 1 (RIPK1), and RIPK3. To definitively address the pathogenic role of necroptosis in ALS, we genetically ablated the critical terminal executioner of necroptosis, mixed lineage kinase domain-like protein (MLKL), in SOD1 G93A mice. Disease onset, progression, and survival were not affected in SOD1 G93A mice lacking MLKL. Motor neuron degeneration and activation of neuroinflammatory cells, astrocytes, and microglia, were independent of MLKL expression in SOD1 G93A mice. While RIPK1 accumulation occurred in spinal cords of SOD1 G93A mice in late stage disease, RIPK3 and MLKL expression levels were not detected in central nervous system tissues from normal or SOD1 G93A mice at any disease stage. These findings demonstrate that necroptosis does not play an important role in motor neuron death in ALS, which may limit the potential of therapeutic targeting of necroptosis in the treatment of neurological disorders.
Inflammation and neuronal death in the motor cortex of the wobbler mouse, an ALS animal model
Journal of Neuroinflammation, 2015
Background: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder of the upper and lower motor neurons, characterized by rapid progressive weakness, muscle atrophy, dysarthria, dysphagia, and dyspnea. Whereas the exact cause of ALS remains uncertain, the wobbler mouse (phenotype WR; genotype wr/wr) equally develops a progressive degeneration of motor neurons in the spinal cord and motor cortex with striking similarities to sporadic human ALS, suggesting the possibility of a common pathway to cell death. Methods: With the aid of immunohistochemistry, confocal laser scanning microscopy, and transmission electron microscopy techniques, we analyze the proliferation behavior of microglial cells and astrocytes. We also investigate possible motor neuron death in the mouse motor cortex at different stages of the wobbler disease, which so far has not received much attention. Results: An abnormal density of Iba-1-positive microglial cells expressing pro-inflammatory tumor necrosis factor (TNF) alpha-and glial fibrillary acidic protein (GFAP)-positive activated astroglial cells was detected in the motor cortex region of the WR mouse 40 days postnatal (d.p.n.). Motor neurons in the same area show caspase 3 activation indicating neurodegenerative processes, which may cause progressive paralysis of the WR mice. It could also cause cell degeneration, such as vacuolization, dilation of the ER, and swollen mitochondria at the same time, and support the assumption that inflammation might be an important contributing factor of motor neuron degeneration. This would appear to be confirmed by the fact that there was no conspicuous increase of microglial cells and astrocytes in the motor cortex of control mice at any time. Conclusions: Activated microglial cells secrete a variety of pro-inflammatory and neurotoxic factors, such as TNF alpha, which could initiate apoptotic processes in the affected wobbler motor neurons, as reflected by caspase 3 activation, and thus, the neuroinflammatory processes might influence or exacerbate the neurodegeneration. Although it remains to be clarified whether the immune response is primary or secondary and how harmful or beneficial it is in the WR motor neuron disease, anti-inflammatory treatment might be considered.
Medical Hypotheses, 2020
Necroptosis is emerging among possible mechanisms underlying cell death in neurodegenerative diseases. In this line, we hypothesize that necroptosis might be implicated in neuronal cell death in amyotrophic lateral sclerosis (ALS). To support this hypothesis, we hereby provide pilot data as well as some findings from the literature about the expression of key markers of the necroptotic pathway in ALS. Our preliminary data indicate the upregulation of key markers of necroptosis activation in lower motor neurons of the spinal cord. These human-derived data combined with some clinical and preclinical findings support our hypothesis testing the involvement of necroptosis in lower motor neurons death in ALS patients. These results pave the way to deepen the role of necroptosis in ALS using both preclinical and clinical approaches. If confirmed, this hypothesis might raise new interventional strategies to alleviate neurodegenerative process in ALS.
The role of excitotoxicity in the pathogenesis of amyotrophic lateral sclerosis
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 2006
Unfortunately and despite all efforts, amyotrophic lateral sclerosis (ALS) remains an incurable neurodegenerative disorder characterized by the progressive and selective death of motor neurons. The cause of this process is mostly unknown, but evidence is available that excitotoxicity plays an important role. In this review, we will give an overview of the arguments in favor of the involvement of excitotoxicity in ALS. The most important one is that the only drug proven to slow the disease process in humans, riluzole, has anti-excitotoxic properties. Moreover, consumption of excitotoxins can give rise to selective motor neuron death, indicating that motor neurons are extremely sensitive to excessive stimulation of glutamate receptors. We will summarize the intrinsic properties of motor neurons that could render these cells particularly sensitive to excitotoxicity. Most of these characteristics relate to the way motor neurons handle Ca 2+ , as they combine two exceptional characteristics: a low Ca 2+ -buffering capacity and a high number of Ca 2+ -permeable AMPA receptors. These properties most likely are essential to perform their normal function, but under pathological conditions they could become responsible for the selective death of motor neurons. In order to achieve this worstcase scenario, additional factors/mechanisms could be required. In 1 to 2% of the ALS patients, mutations in the SOD1 gene could shift the balance from normal motor neuron excitation to excitotoxicity by decreasing glutamate uptake in the surrounding astrocytes and/or by interfering with mitochondrial function. We will discuss point by point these different pathogenic mechanisms that could give rise to classical and/or slow excitotoxicity leading to selective motor neuron death.
Necroptosis Drives Motor Neuron Death in Models of Both Sporadic and Familial ALS
Neuron, 2014
Most cases of neurodegenerative diseases are sporadic, hindering the use of genetic mouse models to analyze disease mechanisms. Focusing on the motor neuron (MN) disease amyotrophic lateral sclerosis (ALS), we therefore devised a fully humanized coculture model composed of human adult primary sporadic ALS (sALS) astrocytes and human embryonic stem-cell-derived MNs. The model reproduces the cardinal features of human ALS: sALS astrocytes, but not those from control patients, trigger selective death of MNs. The mechanisms underlying this noncell-autonomous toxicity were investigated in both astrocytes and MNs. Although causal in familial ALS (fALS), SOD1 does not contribute to the toxicity of sALS astrocytes. Death of MNs triggered by either sALS or fALS astrocytes occurs through necroptosis, a form of programmed necrosis involving receptorinteracting protein 1 and the mixed lineage kinase domain-like protein. The necroptotic pathway therefore constitutes a potential therapeutic target for this incurable disease.
Brain research, 2009
We investigated the effect of Cerebrospinal Fluid (CSF) from sporadic Amyotrophic Lateral Sclerosis patients (SALS-CSF) on motor neuron-like cells to delineate the pathomechanism of SALS. Exposure of NSC-34 cells to SALS-CSF caused lower viability, reduction in differentiation and enhanced lactate dehydrogenase activity. Additionally, reduced choline acetyl transferase expression alongside intracellular aggregation of phosphorylated neurofilaments was prominently seen. The aggregates were immunopositive for ubiquitin. These findings are comparable to the pathological changes seen in the postmortem tissue of ALS patients.
Current view and perspectives in amyotrophic lateral sclerosis
Neural regeneration research, 2017
Amyotrophic lateral sclerosis (ALS), identified as a distinct clinical entity by Charcot since the end of the nineteenth century, is a devastating and fatal neurodegenerative disorder that affects motor neurons in the brain, brainstem and spinal cord. Survival of patients with ALS is associated with several factors such as clinical phenotype, age at onset, gender, early presence of respiratory failure, weight loss and treatment with Riluzole (the only disease-modifying drug approved for this disease). Nowadays, there is still no curative treatment for ALS: palliative care and symptomatic treatment are therefore essential components in the management of these patients. Nevertheless, the scientific knowledge in the field of ALS motor neuron degeneration is growing, with the prospect of new treatments. Based on this physiopathological knowledge, several new therapeutic targets are being studied, involving various mechanisms such as excitotoxicity, neuroinflammation, mitochondrial dysfu...