Optimal methods to characterize the G93A mouse model of ALS

Miana-Mena, Francisco Javier; Muñoz, Marı́a Jesús; Yagüe, G.; Mendez, Mario F.; Moreno, María Ángeles Esteban; Ciriza, Jesús; Zaragoza, Pilar; Osta, Rosario

doi:10.1080/14660820510026162

Cited by 87 publications

(97 citation statements)

References 11 publications

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“…Several studies using a modified hanging wire test found that SOD1-G93A and control mice perform similarly from 56 days of age until time-to-fall latencies of SOD1-G93A mice decrease significantly at 98 days of age (Weydt et al;Miana-Mena et al, 2005). In contrast, other studies revealed long-standing deficits apparent at earlier time-points.…”

Section: Fore-and Hindlimb Motor Deficitsmentioning

confidence: 76%

“…Maximal force exerted by two hindlimb muscles, measured via tetanic contraction, was significantly reduced at 90 days of age in SOD1-G93A mice when compared to control mice (Sharp et al, 2005). Physiological indications of muscle denervation (positive sharp waves and spontaneous fibrillation potentials), were detected in SOD1-G93A mice at 84 days of age (Miana-Mena et al, 2005).…”

Section: Fore-and Hindlimb Motor Deficitsmentioning

confidence: 84%

“…As mentioned above, there are 2 transgenic lines of SOD1-G93A mice that differ in disease onset and progression. Within-line sex-based differences in disease onset and progression have been identified in at least two studies (Miana-Mena et al, 2005;Veldink et al, 2003). Additionally, another SOD1 mutant model carrying the G86R mutation is available for study.…”

Section: Resultsmentioning

confidence: 99%

“…However, the age at which these changes occur differs substantially among published studies. One study reported that both male and female SOD1-G93A mice consistently weighed significantly less than control mice from 14 days of age (Miana-Mena et al, 2005). Growth rates for SOD1-G93A and control mice were similar until a decline began in the affected mice at approximately 95 days of age.…”

Section: Body Weightmentioning

confidence: 99%

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Time-course and characterization of orolingual motor deficits in B6SJL-Tg(SOD1-G93A)1Gur/J mice

2008

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Amyotrophic lateral sclerosis (ALS) is a progressive degenerative disease affecting upper and lower motor neurons. Symptom onset may occur in the muscles of the limbs (spinal onset) or those of the head and neck (bulbar onset). Bulbar involvement is particularly important in ALS as it is associated with increased morbidity and mortality. The purpose of this study was to characterize bulbar motor deficits in the SOD1-G93A mouse model of familial ALS. We measured orolingual motor function by placing thirsty mice in a customized operant chamber that allows for measurement of tongue force and lick rhythm as animals lick water from an isometric disc. Testing spanned the pre-symptomatic, symptomatic, and end-stage segments of the disease. Rotarod performance, fore-and hindlimb grip strength, and locomotor activity were also monitored regularly during this period. We found that spinal involvement was apparent first, with both fore-and hindlimb grip strength being affected in SOD1-G93A mice from the onset of testing (64 days of age). Rotarod performance was affected by 71 days of age. Locomotor activity was not affected, even near end-stage. Bulbar involvement appeared much later, with tongue motility being affected by 100 days of age. Tongue force was affected by 115 days of age. To our knowledge, these findings are the first to describe the onset of bulbar v. spinal motor signs and characterize orolingual motor deficits in this preclinical model of ALS.

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Section: Fore-and Hindlimb Motor Deficitsmentioning

confidence: 76%

Section: Fore-and Hindlimb Motor Deficitsmentioning

confidence: 84%

Section: Resultsmentioning

confidence: 99%

Section: Body Weightmentioning

confidence: 99%

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Time-course and characterization of orolingual motor deficits in B6SJL-Tg(SOD1-G93A)1Gur/J mice

2008

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“…The rotarod test was performed to evaluate motor coordination, strength and balance [30,31] in all the animals used in the study (Table 1). Mice were trained three times a week on the rod rotating at 14 rpm, and then tested from 8 to 16 weeks of age, with an arbitrary maximum time of maintenance in the rotating rod of 180 seconds.…”

Section: Locomotion Testsmentioning

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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Adeno‐associated virus–delivered artificial microRNA extends survival and delays paralysis in an amyotrophic lateral sclerosis mouse model

Stoica

Todeasa

Cabrera

et al. 2016

Annals of Neurology

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Objectives Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by loss of motor neurons, resulting in progressive muscle weakness, paralysis and death within five years of diagnosis. About 10% of cases are inherited, of which 20% are due to mutations in the superoxide dismutase 1 (SOD1) gene. Riluzole, the only FDA approved ALS drug, prolongs survival by only a few months. Experiments in transgenic ALS mouse models have shown decreasing levels of mutant SOD1 protein as a potential therapeutic approach. We sought to develop an efficient AAV mediated RNAi gene therapy for ALS. Methods A single stranded AAV9 vector encoding an artificial microRNA against human SOD1 was injected into the cerebral lateral ventricles of neonatal SOD1G93A mice and impact on disease progression and survival assessed. Results This therapy extended median survival by 50% and delayed hindlimb paralysis, with animals remaining ambulatory until the humane endpoint, which was due to rapid body weight loss. AAV9-treated SOD1G93A mice showed reduction of mutant human SOD1 mRNA levels in upper and lower motor neurons and significant improvements in multiple parameters including the numbers of spinal motor neurons, diameter of ventral root axons, and extent of neuroinflammation in the SOD1G93A spinal cord. Mice also showed previously unexplored changes in pulmonary function, with AAV9-treated SOD1G93A mice displaying a phenotype reminiscent of patient pathophysiology. Interpretation These studies clearly demonstrate that an AAV9-delivered SOD1-specific artificial microRNA is an effective and translatable therapeutic approach for ALS.

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Optimal methods to characterize the G93A mouse model of ALS

Cited by 87 publications

References 11 publications

Time-course and characterization of orolingual motor deficits in B6SJL-Tg(SOD1-G93A)1Gur/J mice

Time-course and characterization of orolingual motor deficits in B6SJL-Tg(SOD1-G93A)1Gur/J mice

Resveratrol Improves Motoneuron Function and Extends Survival in SOD1G93A ALS Mice

Adeno‐associated virus–delivered artificial microRNA extends survival and delays paralysis in an amyotrophic lateral sclerosis mouse model

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