Impairment of mitochondrial function in skeletal muscle of patients with amyotrophic lateral sclerosis

Wiedemann, Falk R.; Winkler, Kirstin; Kuznetsov, Andrey V.; Bartels, Claudius; Vielhaber, Stefan; Feistner, Helmut; Kunz, Wolfram S.

doi:10.1016/s0022-510x(98)00008-2

Cited by 233 publications

(162 citation statements)

References 23 publications

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“…Under oxidative stress the mitochondria morphology changes; they become smaller, their crests disrupted; edema, crystolysis and vacuolization abrade them, while their membranes break down 15 . All these features are not limited to the motor neurons; similar changes were found in liver 16 and muscle 17 cells and in lymphocytes 18 of SALS patients. More recently, we have described similar mitochondrial changes in skin cells from these patients 19 .…”

Section: Sporadic Alssupporting

confidence: 66%

Sporadic amyotrophic lateral sclerosis: new hypothesis regarding its etiology and pathogenesis suggests that astrocytes might be the primary target hosting a still unknown external agent

Sica¹,

Nicola²,

Deniselle³

et al. 2011

Arq. Neuro-Psiquiatr.

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This article briefly describes the already known clinical features and pathogenic mechanisms underlying sporadic amyotrophic lateral sclerosis, namely excitoxicity, oxidative stress, protein damage, inflammation, genetic abnormalities and neuronal death. Thereafter, it puts forward the hypothesis that astrocytes may be the cells which serve as targets for the harmful action of a still unknown environmental agent, while neuronal death may be a secondary event following the initial insult to glial cells. The article also suggests that an emergent virus or a misfolded infectious protein might be potential candidates to accomplish this task. Key words: ALS, SALS, pathogenesis, astrocytes.Esclerosis lateral amiotrófica esporádica: nueva hipótesis relacionada con su etiología y patogenia que sugiere que los astrocitos podrían ser el blanco primario alojando un agente nocivo aun desconocido RESUMEN El artículo presente describe, brevemente, las características clínicas y los mecanismos patogénicos de la esclerosis lateral amiotrófica esporádica, tales como la excitotoxicidad, el stress oxidativo, el daño proteico, la inflamación, las anormalidades genéticas y la muerte neuronal. Luego de ello, sugiere la posibilidad hipotética de que los astrocitos podrían ser el blanco primario de la acción de una agente ambiental, externo, aún desconocido, y que la muerte neuronal aconteciera secundariamente a ese daño astrocitario inicial. El artículo concluye discutiendo la posibilidad de que un virus ambiental o endógeno o una proteína mal plegada, que adquiriera características de infectividad, puedan ser la causa de la enfermedad. Palabras-clave: esclerosis lateral amiotrófica, esclerosis lateral amiotrófica esporádica, patogenia, astrocito.

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Section: Sporadic Alssupporting

confidence: 66%

Sporadic amyotrophic lateral sclerosis: new hypothesis regarding its etiology and pathogenesis suggests that astrocytes might be the primary target hosting a still unknown external agent

Sica¹,

Nicola²,

Deniselle³

et al. 2011

Arq. Neuro-Psiquiatr.

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“…Using cybrid technology, Swerdlow et al reported a decrease in complex I, III and IV activities in platelets isolated from sporadic ALS patients (Bowling et al 1993;Browne et al 1998;Swerdlow et al 1998). Similarly, a decrease in complex I activity was detected in muscle biopsy from sporadic ALS patients (Wiedemann et al 1998;Vielhaber et al 2000). Furthermore, a decrease in complex IV activity was detected in spinal cords of patients that had died of ALS (Fujita et al 1996;Borthwick et al 1999).…”

Section: Discussionmentioning

confidence: 98%

“…ETC activities have been measured as a functional indicator of mitochondria. Several previous studies reported changes in mitochondrial ETC activities in ALS (Bowling et al 1993;Browne et al 1998;Swerdlow et al 1998;Wiedemann et al 1998;Borthwick et al 1999). However, no systematic measurement of ETC activities has been carried out in the spinal cord along the course of disease progression.…”

mentioning

confidence: 99%

Mitochondrial electron transport chain complex dysfunction in a transgenic mouse model for amyotrophic lateral sclerosis

Jung

Higgins

2002

Journal of Neurochemistry

183

111

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Amyotrophic lateral sclerosis is a fatal neurodegenerative disease that causes degeneration of motoneurons. Mutation of Cu,Zn superoxide dismutase (SOD1) is one cause for this disease. In mice, expression of mutant protein causes motoneuron degeneration and paralysis resembling the human disease. Morphological change, indicative of mitochondrial damage, occurs at early stages of the disease. To determine whether mitochondrial function changes during the course of disease progression, enzyme activities of mitochondrial electron transport chain in spinal cords from mice at different disease stages were measured using three different methods: spectrophotometric assay, in situ histochemical enzyme assay, and blue native gel electrophoresis combined with in-gel histochemical reaction. The enzyme activities were decreased in the spinal cord, particularly in the ventral horn, beginning at early disease stages. This decrease persisted throughout the course of disease progression. This decrease was not detected in the spinal cords of non-transgenic animals, of mice expressing the wild-type protein, and in cerebellum and dorsal horn of the spinal cords from mice expressing mutant protein. These results demonstrate a functional defect in mitochondria in the ventral horn region and support the view that mitochondrial damage plays a role in mutant SOD1-induced motoneuron degeneration pathway.

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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]. Resveratrol improves mitochondrial function and induces biogenesis, although there is some controversy about whether this effect is mediated by AMPK activation [18] or by Sirt1 [16,68].…”

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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Impairment of mitochondrial function in skeletal muscle of patients with amyotrophic lateral sclerosis

Cited by 233 publications

References 23 publications

Sporadic amyotrophic lateral sclerosis: new hypothesis regarding its etiology and pathogenesis suggests that astrocytes might be the primary target hosting a still unknown external agent

Sporadic amyotrophic lateral sclerosis: new hypothesis regarding its etiology and pathogenesis suggests that astrocytes might be the primary target hosting a still unknown external agent

Mitochondrial electron transport chain complex dysfunction in a transgenic mouse model for amyotrophic lateral sclerosis

Resveratrol Improves Motoneuron Function and Extends Survival in SOD1G93A ALS Mice

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