Skeletal Muscle Is a Primary Target of SOD1G93A-Mediated Toxicity

Dobrowolny, Gabriella; Aucello, Michela; Rizzuto, Emanuele; Beccafico, Sara; Mammucari, Cristina; Bonconpagni, Simona; Belia, Silvia; Wannenes, Francesca; Nicoletti, Carmine; Prete, Zaccaria Del; Rosenthal, Nadia; Molinaro, Mario; Protasi, Feliciano; Fanò, Giorgio; Sandri, Marco; Musarò, Antonio

doi:10.1016/j.cmet.2008.09.002

Cited by 430 publications

(417 citation statements)

References 40 publications

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“…It has been reported that muscle degeneration can cause denervation and some degenerative changes in motor neurons, including axon terminal degeneration and microgliosis in the spinal cord (71)(72)(73). However, most studies also demonstrate that muscle degeneration is not a primary driver for motor neuron death to the degree observed in ALS (71,72,74,75). Although one study suggested that mutant SOD1 expressed in muscles could drive motor neuron loss (73), the evidence was equivocal and inconsistent with the conclusions of other studies.…”

Section: Mice Expressing Amir-tdp43 Develop Neurodegeneration In Layer Vcontrasting

confidence: 43%

“…Therefore, it is possible that the muscle degeneration contributed to motor neuron dysfunction and degeneration. It has been reported that muscle degeneration can cause denervation and some degenerative changes in motor neurons, including axon terminal degeneration and microgliosis in the spinal cord (71)(72)(73). However, most studies also demonstrate that muscle degeneration is not a primary driver for motor neuron death to the degree observed in ALS (71,72,74,75).…”

Section: Mice Expressing Amir-tdp43 Develop Neurodegeneration In Layer Vmentioning

confidence: 90%

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Partial loss of TDP-43 function causes phenotypes of amyotrophic lateral sclerosis

Yang

Wang

Qiao

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

149

121

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Amyotrophic lateral sclerosis (ALS) is a fatal neurological disease that causes motor neuron degeneration, progressive motor dysfunction, paralysis, and death. Although multiple causes have been identified for this disease, >95% of ALS cases show aggregation of transactive response DNA binding protein (TDP-43) accompanied by its nuclear depletion. Therefore, the TDP-43 pathology may be a converging point in the pathogenesis that originates from various initial triggers. The aggregation is thought to result from TDP-43 misfolding, which could generate cellular toxicity. However, the aggregation as well as the nuclear depletion could also lead to a partial loss of TDP-43 function or TDP-43 dysfunction. To investigate the impact of TDP-43 dysfunction, we generated a transgenic mouse model for a partial loss of TDP-43 function using transgenic RNAi. These mice show ubiquitous transgene expression and TDP-43 knockdown in both the periphery and the central nervous system (CNS). Strikingly, these mice develop progressive neurodegeneration prominently in cortical layer V and spinal ventral horn, motor dysfunction, paralysis, and death. Furthermore, examination of splicing patterns of TDP-43 target genes in human ALS revealed changes consistent with TDP-43 dysfunction. These results suggest that the CNS, particularly motor neurons, possess a heightened vulnerability to TDP-43 dysfunction. Additionally, because TDP-43 knockdown predominantly occur in astrocytes in the spinal cord of these mice, our results suggest that TDP-43 dysfunction in astrocytes is an important driver for motor neuron degeneration and clinical phenotypes of ALS.

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Section: Mice Expressing Amir-tdp43 Develop Neurodegeneration In Layer Vcontrasting

confidence: 43%

Section: Mice Expressing Amir-tdp43 Develop Neurodegeneration In Layer Vmentioning

confidence: 90%

Partial loss of TDP-43 function causes phenotypes of amyotrophic lateral sclerosis

Yang

Wang

Qiao

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

149

121

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“…Dobrowolny et ses collaborateurs confirment le rôle crucial de l'expression musculaire de la SOD1m dans la pathologie [42]. …”

Section: Note Ajoutée Aux éPreuvesunclassified

Sclérose latérale amyotrophique, jonction neuromusculaire et déficit énergétique

Dupuis

Loeffler

2008

Med Sci (Paris)

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La sclérose latérale amyotrophique (SLA) est la maladie du motoneurone de l'adulte la plus répandue avec entre 1 et 3 nouveaux cas par an pour 100 000 personnes dans le monde. À ce titre, elle est la maladie neurodégénérative la plus fréquente après les maladies d'Alzheimer et de Parkinson. La SLA se manifeste par une paralysie progressive qui touche les muscles des membres (formes spinales) ou de la face (formes bulbaires). Le motoneurone inférieur, qui innerve les muscles squelettiques, dégénère et le motoneurone supérieur corticospinal est lui aussi affecté. La plupart des patients décèdent en 2 à 5 ans après le diagnostic, mais la maladie est très hétérogène tant dans sa durée que dans sa présentation clinique. Les options thé-rapeutiques sont quasi inexistantes. Ainsi, le riluzole 1 reste à ce jour la seule molécule dont l'efficacité est prouvée, mais il n'augmente la survie des patients que de quelques mois. La SLA se présente sous une forme familiale dans 20 % des cas, le plus souvent de transmission autosomique dominante, ou sous une forme sporadique car non associée à une histoire familiale connue. Il convient de noter que les formes familiales et sporadiques ne se distinguent pas sur le plan clinique. Au sein d'une même famille affectée, la présentation clinique de la maladie est hétérogène, ce qui souligne l'importance du contexte environnemental et suggère l'existence de gènes modulateurs de la pathologie. Plusieurs gènes, dont ceux codant pour l'angiogénine et la senataxine, et les gènes vapb (VAMP/synaptobrevin-associated membrane protein B) ou, plus récemment, tdp43 (TAR DNA-binding protein 43), ont été associés à des formes familiales, mais les mécanismes qui expliquent la dégénérescence sélective des motoneurones dans ces cas particuliers de SLA ne sont pas encore résolus [1,2]. À l'inverse, le premier gène dont des mutations ont été liées à la SLA, le gène sod1, a, en revanche, été largement étudié. L'objectif de cette revue est de résumer les données les plus récentes concernant les 1 Riluzole : agit en bloquant les canaux sodiques dépendant du voltage et en diminuant ainsi la libération présynaptique du glutamate.> La sclérose latérale amyotrophique (SLA) est la maladie du motoneurone de l'adulte la plus fréquente. Une partie des cas de SLA est liée à des mutations du gène codant la superoxyde dismutase à cuivre/zinc (SOD1) et l'analyse phénotypique de souris transgéniques exprimant des formes mutées de SOD1 (SOD1m) a permis de mieux comprendre les mécanismes physiopathologiques entraînant la mort du motoneurone. En revanche, l'extrapolation des résultats obtenus avec ces souris transgéniques s'est révélée décevante lors de plusieurs essais cliniques. Dans cette synthèse, nous résumons les principales données de la littérature concernant les mécanismes physiopathologiques à l'oeuvre chez les souris SOD1m. En particulier, nous montrons comment en quelques années, les recherches ont mis en évidence que la degénérescence du motoneurone a lieu de façon rétrograde, via une déstabilisation initiale...

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“…38,39 Similarly, increased autophagy levels in a transgenic mouse model expressing a mutant Sod1 (superoxide dismutase 1, soluble) gene that mediates antioxidative defense are associated with muscle atrophy and a profound reduction in muscle strength. 40 In centronuclear myopathy, a naturally occurring mutation leading to inactivation of MTMR14/hJumpy (myotubularin-related protein 14) activates autophagy, suggesting that aggravated autophagy is important in the etiology of centronuclear myopathy. 41 Excessive autophagy contributing to muscle wasting has also been shown in tumor-bearing animals, 42 in a systemic burn injury model in mice, 43 in patients with progressive stages of lung cancer cachexia, 44 and in chronic obstructive pulmonary disease patients.…”

Section: Basic Conceptsmentioning

confidence: 99%

Heat shock response and autophagy—cooperation and control

2015

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Abbreviations: AKT, v-akt murine thymoma viral oncogene homolog 1; AMPK, adenosine monophosphate-activated protein kinase; ATG, autophagy-related; BECN1, Beclin 1, autophagy related; EIF4EBP1, eukaryotic translation initiation factor 4E binding protein 1; ER, endoplasmic reticulum; FOXO, forkhead box O; HSF1, heat shock transcription factor 1; HSP, heat shock protein; HSPA8/ HSC70, heat shock 70kDa protein 8; IL, interleukin; LC3, MAP1LC3, microtubule-associated protein 1 light chain 3; MTMR14/ hJumpy, myotubularin related protein 14; MTOR, mechanistic target of rapamycin; NR1D1/Rev-Erb-a, nuclear receptor subfamily 1, group D, member 1; PBMC, peripheral blood mononuclear cell; PPARGC1A/PGC-1a, peroxisome proliferator-activated receptor, gamma, coactivator 1 a; RHEB, Ras homolog enriched in brain; SOD, superoxide dismutase; SQSTM1/p62, sequestosome 1; TPR, translocated promoter region, nuclear basket protein; TSC, tuberous sclerosis complex; ULK1, unc-51 like autophagy activating kinase 1.Protein quality control (proteostasis) depends on constant protein degradation and resynthesis, and is essential for proper homeostasis in systems from single cells to whole organisms. Cells possess several mechanisms and processes to maintain proteostasis. At one end of the spectrum, the heat shock proteins modulate protein folding and repair. At the other end, the proteasome and autophagy as well as other lysosome-dependent systems, function in the degradation of dysfunctional proteins. In this review, we examine how these systems interact to maintain proteostasis. Both the direct cellular data on heat shock control over autophagy and the time course of exercise-associated changes in humans support the model that heat shock response and autophagy are tightly linked. Studying the links between exercise stress and molecular control of proteostasis provides evidence that the heat shock response and autophagy coordinate and undergo sequential activation and downregulation, and that this is essential for proper proteostasis in eukaryotic systems.

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Skeletal Muscle Is a Primary Target of SOD1G93A-Mediated Toxicity

Cited by 430 publications

References 40 publications

Partial loss of TDP-43 function causes phenotypes of amyotrophic lateral sclerosis

Partial loss of TDP-43 function causes phenotypes of amyotrophic lateral sclerosis

Sclérose latérale amyotrophique, jonction neuromusculaire et déficit énergétique

Heat shock response and autophagy—cooperation and control

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