Molecular pathways of motor neuron injury in amyotrophic lateral sclerosis

Ferraiuolo, Laura; Kirby, Janine; Grierson, Andrew J.; Sendtner, Michael; Shaw, Pamela J.

doi:10.1038/nrneurol.2011.152

Cited by 516 publications

(460 citation statements)

References 191 publications

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“…Although there is no consensus about the exact role of mitochondrial abnormalities [61], it is accepted that mitochondrial dysfunction is an important hallmark of ALS pathogenesis [5,62,63]. Several authors have shown deficits in mitochondrial function in the spinal cord and muscles of both human patients [64] and animal models of ALS [65][66][67].…”

Section: Discussionmentioning

confidence: 99%

Resveratrol Improves Motoneuron Function and Extends Survival in SOD1G93A ALS Mice

et al. 2014

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Amyotrophic lateral sclerosis (ALS) is an adult onset neurodegenerative disease that causes progressive paralysis and death due to degeneration of motoneurons in spinal cord, brainstem and motor cortex. Nowadays, there is no effective therapy and patients die 2-5 years after diagnosis. Resveratrol (trans-3,4′,5-trihydroxystilbene) is a natural polyphenol found in grapes, with promising neuroprotective effects since it induces expression and activation of several neuroprotective pathways involving Sirtuin1 and AMPK. The objective of this work was to assess the effect of resveratrol administration on SOD1 G93A ALS mice. We determined the onset of symptoms by rotarod test and evaluated upper and lower motoneuron function using electrophysiological tests.We assessed the survival of the animals and determined the number of spinal motoneurons. Finally, we further investigated resveratrol mechanism of action by means of western blot and immunohistochemical analysis. Resveratrol treatment from 8 weeks of age significantly delayed disease onset and preserved lower and upper motoneuron function in female and male animals. Moreover, resveratrol significantly extended SOD1 G93A mice lifespan and promoted survival of spinal motoneurons. Delayed resveratrol administration from 12 weeks of age also improved spinal motoneuron function preservation and survival. Further experiments revealed that resveratrol protective effects were associated with increased expression and activation of Sirtuin 1 and AMPK in the ventral spinal cord. Both mediators promoted normalization of the autophagic flux and, more importantly, increased mitochondrial biogenesis in the SOD1 G93A spinal cord. Taken together, our findings suggest that resveratrol may represent a promising therapy for ALS.

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Section: Discussionmentioning

confidence: 99%

Resveratrol Improves Motoneuron Function and Extends Survival in SOD1G93A ALS Mice

et al. 2014

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“…As in other disorders, the damage of these neurons occurs by the combination of excitotoxicity, chronic inflammation, oxidative stress, protein aggregation, and other cytotoxic events [146][147][148]. The most abundant cases of ALS are sporadic [149], but the disease may be also familiar, associated with mutations in genes encoding for superoxide dismutase-1 (SOD-1), TAR-DNA binding protein-43 (TDP-43) or FUS (fused in sarcoma) protein, as well as the more recent CCGGGG hexanucleotide expansion in C9orf72 [145,148].…”

Section: Cannabinoids and Chronic Neurodegenerative Disorders: IV Alsmentioning

confidence: 99%

Cannabinoids in Neurodegenerative Disorders and Stroke/Brain Trauma: From Preclinical Models to Clinical Applications

2015

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Cannabinoids form a singular family of plantderived compounds (phytocannabinoids), endogenous signaling lipids (endocannabinoids), and synthetic derivatives with multiple biological effects and therapeutic applications in the central and peripheral nervous systems. One of these properties is the regulation of neuronal homeostasis and survival, which is the result of the combination of a myriad of effects addressed to preserve, rescue, repair, and/or replace neurons, and also glial cells against multiple insults that may potentially damage these cells. These effects are facilitated by the location of specific targets for the action of these compounds (e.g., cannabinoid type 1 and 2 receptors, endocannabinoid inactivating enzymes, and nonendocannabinoid targets) in key cellular substrates (e.g., neurons, glial cells, and neural progenitor cells). This potential is promising for acute and chronic neurodegenerative pathological conditions. In this review, we will collect all experimental evidence, mainly obtained at the preclinical level, supporting that different cannabinoid compounds may be neuroprotective in adult and neonatal ischemia, brain trauma, Alzheimer's disease, Parkinson's disease, Huntington's chorea, and amyotrophic lateral sclerosis. This increasing experimental evidence demands a prompt clinical validation of cannabinoid-based medicines for the treatment of all these disorders, which, at present, lack efficacious treatments for delaying/arresting disease progression, despite the fact that the few clinical trials conducted so far with these medicines have failed to demonstrate beneficial effects.

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“…As a result of this degenerative process, most patients usually die from respiratory failure within 3–5 years from the onset of symptoms 1, 2 . The etiology and mechanisms underlying this debilitating disease are not fully understood, and hence, there is currently no curative or disease-halting therapy for this disorder.…”

Section: Introductionmentioning

confidence: 99%

ANGDelMut – a web-based tool for predicting and analyzing functional loss mechanisms of amyotrophic lateral sclerosis-associated angiogenin mutations

et al. 2013

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ANGDelMut is a web-based tool for predicting the functional consequences of missense mutations in the angiogenin (ANG) protein, which is associated with amyotrophic lateral sclerosis (ALS). Missense mutations in ANG result in loss of either ribonucleolytic activity or nuclear translocation activity or both of these functions, and in turn cause ALS. However, no web-based tools are available to predict whether a newly identified ANG mutation will possibly lead to ALS. More importantly, no web-implemented method is currently available to predict the mechanisms of loss-of-function(s) of ANG mutants. In light of this observation, we developed the ANGDelMut web-based tool, which predicts whether an ANG mutation is deleterious or benign. The user selects certain attributes from the input panel, which serves as a query to infer whether a mutant will exhibit loss of ribonucleolytic activity or nuclear translocation activity or whether the overall stability will be affected. The output states whether the mutation is deleterious or benign, and if it is deleterious, gives the possible mechanism(s) of loss-of-function. This web-based tool, freely available at http://bioschool.iitd.ernet.in/DelMut/, is the first of its kind to provide a platform for researchers and clinicians, to infer the functional consequences of ANG mutations and correlate their possible association with ALS ahead of experimental findings.

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Molecular pathways of motor neuron injury in amyotrophic lateral sclerosis

Cited by 516 publications

References 191 publications

Resveratrol Improves Motoneuron Function and Extends Survival in SOD1G93A ALS Mice

Resveratrol Improves Motoneuron Function and Extends Survival in SOD1G93A ALS Mice

Cannabinoids in Neurodegenerative Disorders and Stroke/Brain Trauma: From Preclinical Models to Clinical Applications

ANGDelMut – a web-based tool for predicting and analyzing functional loss mechanisms of amyotrophic lateral sclerosis-associated angiogenin mutations

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