The changing scene of amyotrophic lateral sclerosis

Robberecht, Wim; Philips, Thomas

doi:10.1038/nrn3430

Cited by 859 publications

(819 citation statements)

References 235 publications

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“…Sirt1 is a NAD + -dependent deacetylase that plays an important role regulating cell metabolism and has recently been postulated as a neuroprotective element in several neurodegenerative disorders [13]. Sirt1 induces protective effects since it is upstream of multiple effectors that participate in several cell processes, such as inflammation [43], autophagy [45] and mitochondrial function [16,46], all of them related to ALS physiopathology [5,56]. In the present work, we found that Sirt1 was overexpressed in spinal MNs of SOD1 G93A mice after resveratrol administration.…”

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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“…Amyotrophic lateral sclerosis (ALS) is a devastating age-related neurodegenerative disease characterised by a progressive loss of motor neurons of the central nervous system, leading to progressive muscle denervation and paralysis [1]. No effective therapy is available for ALS, and understanding the disease pathogenesis could help in developing effective treatments.…”

Section: Introductionmentioning

confidence: 99%

SOD1 stimulates lamellipodial protrusions in Neuro 2A cell lines

Ferrari

Verpelli

Crespi

et al. 2018

Communicative & Integrative Biology

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We here investigated the effects of overexpressed superoxide dismutase (SOD)1 and amyotrophic lateral sclerosis (ALS)-linked SOD1 mutants G93A and G147S in Neuro 2A (N2A) cell lines, and found a three-fold increase in lamellipodia either in cells cultured under differentiated or undifferentiated growth conditions. In undifferentiated N2A cells, SOD1 constructs promoted lamellipodial protrusions to similar extent as the overexpression of Rac1, and SOD1-mediated lamellipodia were prevented by coexpression of the N17 dominant-negative form of Rac1, or shRNA for a downstream effector of Rac1, the insulin receptor tyrosine kinase substrate p53 (IRSp53) or its binding partner LIN7. Moreover, no additive effect was measured by coexpression of the SOD1 constructs with Rac1, IRSp53 or LIN7. Collectively these data support a role for SOD1 in the regulation of Rac1-mediated lamellipodia pathway, a property fully retained by the two SOD1 mutants.

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“…Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder affecting motor neurons (MNs) in the cortex, brainstem, and spinal cord that causes weakness and atrophy of skeletal muscles [1]. While traditionally considered a purely motor disease, neuronal abnormalities in the prefrontal and temporal cortex may also lead to frontal executive dysfunction, with about 15 % of patients manifesting frontotemporal dementia [2].…”

Section: Introductionmentioning

confidence: 99%

“…The disease is sporadic in about 85 % of cases and is familial in about 15 % of cases [4]. The average survival is 3-5 years from symptom onset [1]. Riluzole, the only Food and Drug Administration-approved medication for ALS, has at best modest effects [5].…”

Section: Introductionmentioning

confidence: 99%

Recent Advances and the Future of Stem Cell Therapies in Amyotrophic Lateral Sclerosis

2015

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Amyotrophic lateral sclerosis is a progressive neurodegenerative disease of the motor neurons without a known cure. Based on the possibility of cellular neuroprotection and early preclinical results, stem cells have gained widespread enthusiasm as a potential treatment strategy. Preclinical models demonstrate a protective role of engrafted stem cells and provided the basis for human trials carried out using various types of stem cells, as well as a range of cell delivery methods. To date, no trial has demonstrated a clear therapeutic benefit; however, results remain encouraging and are the basis for ongoing studies. In addition, stem cell technology continues to improve, and induced pluripotent stem cells may offer additional therapeutic options in the future. Improved disease models and clinical trials will be essential in order to validate stem cells as a beneficial therapy.

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The changing scene of amyotrophic lateral sclerosis

Cited by 859 publications

References 235 publications

Resveratrol Improves Motoneuron Function and Extends Survival in SOD1G93A ALS Mice

Resveratrol Improves Motoneuron Function and Extends Survival in SOD1G93A ALS Mice

SOD1 stimulates lamellipodial protrusions in Neuro 2A cell lines

Recent Advances and the Future of Stem Cell Therapies in Amyotrophic Lateral Sclerosis

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