Disease progression of human SOD1 (G93A) transgenic ALS model rats

Abstract

The recent development of a rat model of amyotrophic lateral sclerosis (ALS) in which the rats harbor a mutated human SOD1 (G93A) gene has greatly expanded the range of potential experiments, because the rats' large size permits biochemical analyses and therapeutic trials, such as the intrathecal injection of new drugs and stem cell transplantation. The precise nature of this disease model remains unclear. We described three disease phenotypes: the forelimb-, hindlimb-, and general-types. We also established a simple, non-invasive, and objective evaluation system using the body weight, inclined plane test, cage activity, automated motion analysis system (SCANET), and righting reflex. Moreover, we created a novel scale, the Motor score, which can be used with any phenotype and does not require special apparatuses. With these methods, we uniformly and quantitatively assessed the onset, progression, and disease duration, and clearly presented the variable clinical course of this model; disease progression after the onset was more aggressive in the forelimb-type than in the hindlimb-type. More importantly, the disease stages defined by our evaluation system correlated well with the loss of spinal motor neurons. In particular, the onset of muscle weakness coincided with the loss of approximately 50% of spinal motor neurons. This study should provide a valuable tool for future experiments to test potential ALS therapies.

The Complement Factor C5a Contributes to Pathology in a Rat Model of Amyotrophic Lateral Sclerosis

“…The fore limb paralysis phenotype occurred in ϳ25% of the SOD1 G93A rats and resulted in a more aggressive disease course, with an earlier and more variable disease onset and faster progression (motor-deficit duration: 3.1 Ϯ 1.4 days; n ϭ 8), in concordance with other studies (27,28). In our current studies, we excluded rats displaying the altered phenotype of fore limb onset, since these variables may have confounded the interpretation of our data (27).…”

“…To evaluate the disease course in the SOD1 G93A rats, we measured body weight and performed a motor function test, a combination which reliably identifies disease onset and progression and correlates with motor neuron loss (27). Motor function was determined using a modified motor scale (12,27).…”

Intraparenchymal spinal cord delivery of adeno-associated virus IGF-1 is protective in the SOD1G93A model of ALS

“…Sex-specific differences in disease onset and progression [31,40,52,55] and response to therapeutic interventions [16] have been noted in CNS disorders, including ALS. For example, studies with untreated mutant SOD1 mice [31] and rats [52], including results from the present study, demonstrate that disease onset and overall survival occur earlier on average in males.…”

Oscillatory potentials in electroretinogram as an early marker of visual abnormalities in vitamin A deficiency

“…Animals (n=6 for control and VAD rats) were assessed in the SCANET cage for 30 min. Horizontal movements and the frequency of vertical movements caused by rearing were measured as previously described (22).…”