Massive Mitochondrial Degeneration in Motor Neurons Triggers the Onset of Amyotrophic Lateral Sclerosis in Mice Expressing a Mutant SOD1

Kong, Jiming; Xu, Zuoshang

doi:10.1523/jneurosci.18-09-03241.1998

Cited by 638 publications

(478 citation statements)

References 20 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]. 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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Section: Discussionmentioning

confidence: 99%

Resveratrol Improves Motoneuron Function and Extends Survival in SOD1G93A ALS Mice

et al. 2014

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“…For example, several lines of evidence indicate that excessive stimulation of glutamate receptors, perhaps due to impairment to the glutamate-transport system and, in particular, of the astroglial transporter EAAT2, could lead to Ca 2þ overload in mitochondria, resulting in overproduction of ROS and oxidative stress-mediated motor-neuron damage. In addition, motor neurons could become more sensitive to glutamate-mediated excitotoxicity in the presence of mutant SOD1 in mitochondria (76).…”

Section: Discussionmentioning

confidence: 99%

Glutamate Transporters and the Excitotoxic Path to Motor Neuron Degeneration in Amyotrophic Lateral Sclerosis

Foran

Trotti²

2009

Antioxidants & Redox Signaling

254

141

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Responsible for the majority of excitatory activity in the central nervous system (CNS), glutamate interacts with a range of specific receptor and transporter systems to establish a functional synapse. Excessive stimulation of glutamate receptors causes excitotoxicity, a phenomenon implicated in both acute and chronic neurodegenerative diseases [e.g., ischemia, Huntington's disease, and amyotrophic lateral sclerosis (ALS)]. In physiology, excitotoxicity is prevented by rapid binding and clearance of synaptic released glutamate by high-affinity, Na þ -dependent glutamate transporters and amplified by defects to the glutamate transporter and receptor systems. ALS pathogenetic mechanisms are not completely understood and characterized, but excitotoxicity has been regarded as one firm mechanism implicated in the disease because of data obtained from ALS patients and animal and cellular models as well as inferred by the documented efficacy of riluzole, a generic antiglutamatergic drug, has in patients. In this article, we critically review the several lines of evidence supporting a role for glutamate-mediated excitotoxicity in the death of motor neurons occurring in ALS, putting a particular emphasis on the impairment of the glutamate-transport system. Antioxid. Redox Signal. 11, 1587-1602. Glutamate in the Central Nervous SystemL -Glutamate is the predominant excitatory neurotransmitter in the central nervous system (CNS). A nonessential amino acid, glutamate is continuously converted to a-ketoglutarate through deamination by glutamate dehydrogenase or by transamination by one of the transaminases and metabolized through the tricarboxylic acid cycle to succinate, fumarate, and malate, successively. Glutamate is also the product of the deamination of glutamine by phosphateactivated glutaminase, a mitochondrial and possibly neuronspecific enzyme (80). Synaptically released glutamate activates a family of ligand-gated ion channels (ionotropic receptors) and G protein-coupled receptors (metabotropic receptors), and its action is terminated by specific reuptake systems located mainly in astrocytes surrounding the synapse. In astrocytes, glutamate is then converted into glutamine, which does not have neurotransmitter properties and can be released and made available for neurons to convert it back to glutamate through a glutamine-reuptake system. Glutamate is then packed by vesicular glutamate transporters in synaptic vesicles, ready to be released again (35,129) (Fig. 1).

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“…In mice with the ALSlinked G37R SOD1 mutation, the presence in axons and dendrites of membrane-bound vacuoles, which seem to be derived from degenerating mitochondria (5), is noteworthy. Massive mitochondrial degeneration is also observed in motor neurons of G93A SOD1 mutant mice at the onset of the disease (8), when electron transfer chain activity and ATP synthesis appear severely injured (9). Furthermore, a selective decrease in the activity of cytochrome c oxidase, encoded by the mitochondrial genome, occurs in motor neurons of sporadic ALS patients (10), and the reduction in the amount of mitochondrial DNA in the spinal cord of ALS patients correlates with a decrease in the activities of citrate synthase and the respiratory chain complexes IϩIII, IIϩIII, and IV (11).…”

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confidence: 97%

Evidence for defective energy homeostasis in amyotrophic lateral sclerosis: Benefit of a high-energy diet in a transgenic mouse model

Dupuis

Oudart

Frydman

et al. 2004

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

487

472

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Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease characterized by selective loss of motor neurons and progressive muscle wasting. Growing evidence indicates that mitochondrial dysfunction, not only occurring in motor neurons but also in skeletal muscle, may play a crucial role in the pathogenesis. In this regard, the life expectancy of the ALS G93A mouse line is extended by creatine, an intracellular energy shuttle that ameliorates muscle function. Moreover, a population of patients with sporadic ALS exhibits a generalized hypermetabolic state of as yet unknown origin. Altogether, these findings led us to explore whether alterations in energy homeostasis may contribute to the disease process. Here, we show important variations in a number of metabolic indicators in transgenic ALS mice, which in all shows a metabolic deficit. These alterations were accompanied early in the asymptomatic phase of the disease by reduced adipose tissue accumulation, increased energy expenditure, and concomitant skeletal muscle hypermetabolism. Compensating this energetic imbalance with a highly energetic diet extended mean survival by 20%. In conclusion, we suggest that hypermetabolism, mainly of muscular origin, may represent by itself an additional driven force involved in increasing motor neuron vulnerability.

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Massive Mitochondrial Degeneration in Motor Neurons Triggers the Onset of Amyotrophic Lateral Sclerosis in Mice Expressing a Mutant SOD1

Cited by 638 publications

References 20 publications

Resveratrol Improves Motoneuron Function and Extends Survival in SOD1G93A ALS Mice

Resveratrol Improves Motoneuron Function and Extends Survival in SOD1G93A ALS Mice

Glutamate Transporters and the Excitotoxic Path to Motor Neuron Degeneration in Amyotrophic Lateral Sclerosis

Evidence for defective energy homeostasis in amyotrophic lateral sclerosis: Benefit of a high-energy diet in a transgenic mouse model

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