Spinal inhibitory circuits and their role in motor neuron degeneration

Ramírez-Jarquín, Uri Nimrod; Lazo-Gómez, Rafael; Tovar‐y‐Romo, Luis B.; Tapia, Ricardo

doi:10.1016/j.neuropharm.2013.10.003

Cited by 39 publications

(40 citation statements)

References 104 publications

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“…Data shown here and previously (Castillo et al, 2013; Fritz et al, 2013) indicate that independent of neuronal degeneration exposure of spinal cord cultures to toxic ACMs causes pathophysiological changes—including increases in nitroxidative stress, Na v channel activity, neuronal excitability, and intracellular calcium transients—in both motoneurons and interneurons. Moreover, detailed analyses in SOD1-ALS mice also indicate that several pathological changes can be detected in interneurons, and importantly, much before the onset of disease symptoms (Martin et al, 2007; van Zundert et al, 2008, 2012; Ramírez-Jarquín et al, 2013; Wootz et al, 2013). If both types of neurons are affected in ALS, why then are motoneurons killed and interneurons spared?…”

Section: Discussionmentioning

confidence: 99%

Astrocytes expressing mutant SOD1 and TDP43 trigger motoneuron death that is mediated via sodium channels and nitroxidative stress

Rojas

Cortés

Abarzúa

et al. 2014

Front. Cell. Neurosci.

101

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Amyotrophic lateral sclerosis (ALS) is a fatal paralytic disorder caused by dysfunction and degeneration of motor neurons. Multiple disease-causing mutations, including in the genes for SOD1 and TDP-43, have been identified in ALS. Astrocytes expressing mutant SOD1 are strongly implicated in the pathogenesis of ALS: we have shown that media conditioned by astrocytes carrying mutant SOD1G93A contains toxic factor(s) that kill motoneurons by activating voltage-sensitive sodium (Nav) channels. In contrast, a recent study suggests that astrocytes expressing mutated TDP43 contribute to ALS pathology, but do so via cell-autonomous processes and lack non-cell-autonomous toxicity. Here we investigate whether astrocytes that express diverse ALS-causing mutations release toxic factor(s) that induce motoneuron death, and if so, whether they do so via a common pathogenic pathway. We exposed primary cultures of wild-type spinal cord cells to conditioned medium derived from astrocytes (ACM) that express SOD1 (ACM-SOD1G93A and ACM-SOD1G86R) or TDP43 (ACM-TDP43A315T) mutants; we show that such exposure rapidly (within 30–60 min) increases dichlorofluorescein (DCF) fluorescence (indicative of nitroxidative stress) and leads to extensive motoneuron-specific death within a few days. Co-application of the diverse ACMs with anti-oxidants Trolox or esculetin (but not with resveratrol) strongly improves motoneuron survival. We also find that co-incubation of the cultures in the ACMs with Nav channel blockers (including mexiletine, spermidine, or riluzole) prevents both intracellular nitroxidative stress and motoneuron death. Together, our data document that two completely unrelated ALS models lead to the death of motoneuron via non-cell-autonomous processes, and show that astrocytes expressing mutations in SOD1 and TDP43 trigger such cell death through a common pathogenic pathway that involves nitroxidative stress, induced at least in part by Nav channel activity.

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Section: Discussionmentioning

confidence: 99%

Astrocytes expressing mutant SOD1 and TDP43 trigger motoneuron death that is mediated via sodium channels and nitroxidative stress

Rojas

Cortés

Abarzúa

et al. 2014

Front. Cell. Neurosci.

101

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“…Renshaw cell alterations may lead to a hyperexcitable state and eventually motor neuron degeneration. It has been postulated that this hyperexcitability is caused by the loss of the recurrent Renshaw cell-mediated inhibition 83. Alternatively, it is possible that Renshaw cell loss is not an initial causation of motor neuron hyperexcitability and neurodegeneration, but is secondary to motor neuron degeneration 83 84…”

Section: Excitatory and Inhibitory Neurotransmission In Alsmentioning

confidence: 99%

Amyotrophic lateral sclerosis: a long preclinical period?

Eisen

Kiernan

Mitsumoto

et al. 2014

Journal of Neurology, Neurosurgery & Psychiatry

124

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The onset of amyotrophic lateral sclerosis (ALS) is conventionally considered as commencing with the recognition of clinical symptoms. We propose that, in common with other neurodegenerations, the pathogenic mechanisms culminating in ALS phenotypes begin much earlier in life. Animal models of genetically determined ALS exhibit pathological abnormalities long predating clinical deficits. The overt clinical ALS phenotype may develop when safety margins are exceeded subsequent to years of mitochondrial dysfunction, neuroinflammation or an imbalanced environment of excitation and inhibition in the neuropil. Somatic mutations, the epigenome and external environmental influences may interact to trigger a metabolic cascade that in the adult eventually exceeds functional threshold. A long preclinical and subsequent presymptomatic period pose a challenge for recognition, since it offers an opportunity for protective and perhaps even preventive therapeutic intervention to rescue dysfunctional neurons. We suggest, by analogy with other neurodegenerations and from SOD1 ALS mouse studies, that vulnerability might be induced in the perinatal period.

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“…The situation is even more complex than imagined, since growing evidence supports that ALS not only affects motor neurons but also other cells. In the spinal cord, astrocytes and microglial cells, as well as oligodendrocytes and interneurons, which have been more recently implicated, appear to contribute to the degenerative process (84,93,95,120). Other neurons are also affected, such as serotonergic neurons in the brainstem and neurons in the frontal and temporal lobes (28,118).…”

Section: Introductionmentioning

confidence: 99%

The Role of Skeletal Muscle in Amyotrophic Lateral Sclerosis

et al. 2016

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Amyotrophic lateral sclerosis (ALS) is a fatal adult-onset disease primarily characterized by upper and lower motor neuron degeneration, muscle wasting and paralysis. It is increasingly accepted that the pathological process leading to ALS is the result of multiple disease mechanisms that operate within motor neurons and other cell types both inside and outside the central nervous system. The implication of skeletal muscle has been the subject of a number of studies conducted on patients and related animal models. In this review, we describe the features of ALS muscle pathology and discuss on the contribution of muscle to the pathological process. We also give an overview of the therapeutic strategies proposed to alleviate muscle pathology or to deliver curative agents to motor neurons. ALS muscle mainly suffers from oxidative stress, mitochondrial dysfunction and bioenergetic disturbances. However, the way by which the disease affects different types of myofibers depends on their contractile and metabolic features. Although the implication of muscle in nourishing the degenerative process is still debated, there is compelling evidence suggesting that it may play a critical role. Detailed understanding of the muscle pathology in ALS could, therefore, lead to the identification of new therapeutic targets.

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Spinal inhibitory circuits and their role in motor neuron degeneration

Cited by 39 publications

References 104 publications

Astrocytes expressing mutant SOD1 and TDP43 trigger motoneuron death that is mediated via sodium channels and nitroxidative stress

Astrocytes expressing mutant SOD1 and TDP43 trigger motoneuron death that is mediated via sodium channels and nitroxidative stress

Amyotrophic lateral sclerosis: a long preclinical period?

The Role of Skeletal Muscle in Amyotrophic Lateral Sclerosis

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