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A Quick Phenotypic Neurological Scoring System for Evaluating Disease Progression in the SOD1-G93A Mouse Model of ALS
Published on: October 6, 2015
A dynein mutation attenuates motor neuron degeneration in SOD1(G93A) mice
M Teuchert1, D Fischer, B Schwalenstoecker
1Department of Neurology, University of Ulm, Oberer Eselsberg 45, 89081 Ulm, Germany.
Abstract:
Cu/Zn SOD1(G93A) transgenic mice develop phenotypical hallmarks of ALS and serve therefore as an established model to study the molecular mechanisms underlying this disease. Recent reports demonstrate that mutations in the motor protein dynein in Legs at odd angles (Loa) and Cramping (Cra1) mice lead to similar but milder phenotypes. Surprisingly, double transgenic mice (Loa/SOD1(G93A)) have been recently shown to attenuate rather than to accelerate the phenotypical expression of motor neuron degeneration. These results raise the question whether other functional relevant mutations in dynein cause a similar effect. To address this question, we have cross-bred SOD1(G93A) with Cra1/+ mice. These double transgenic mice show an attenuated decline of both motor activity and body weight and an increase of survival time compared to SOD1(G93A) mice. Thus, this study confirms that mechanisms associated with dynein such as retrograde axonal transport may play an important role in SOD1(G93A-) toxicity on motor neurons.
Insights
Mutations in the dynein motor protein in SOD1(G93A) mice, a model for amyotrophic lateral sclerosis (ALS), attenuated motor neuron degeneration. This suggests dynein-associated mechanisms are crucial in ALS pathogenesis.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Cu/Zn SOD1(G93A) transgenic mice are a key model for studying amyotrophic lateral sclerosis (ALS).
- Mutations in the motor protein dynein in mouse models (Loa, Cra1) cause milder neurodegenerative phenotypes.
- Double transgenic mice (Loa/SOD1(G93A)) unexpectedly show attenuated motor neuron degeneration.
Purpose of the Study:
- To investigate if other functional dynein mutations similarly affect SOD1(G93A)-mediated motor neuron degeneration.
- To explore the role of dynein-associated mechanisms in ALS pathogenesis.
Main Methods:
- Cross-breeding SOD1(G93A) mice with Cra1/+ mice to create double transgenic mice.
- Assessing motor activity, body weight decline, and survival time in SOD1(G93A) and double transgenic mice.
Main Results:
- Double transgenic mice (SOD1(G93A)/Cra1) exhibited attenuated decline in motor activity and body weight compared to SOD1(G93A) mice.
- Survival time was significantly increased in the double transgenic mice.
- These findings support a protective role for certain dynein mutations against SOD1(G93A) toxicity.
Conclusions:
- Dynein-associated mechanisms, potentially including retrograde axonal transport, play a significant role in the toxicity of SOD1(G93A) in motor neurons.
- Modulating dynein function may offer therapeutic strategies for ALS.
