Sarah Schram1, Donald Chuang2, Greg Schmidt2, Hristo Piponov2, Cory Helder2, James Kerns2, Mark Gonzalez2, Fei Song3, Jeffrey A Loeb4. 1. Department of Neurology and Rehabilitation, Graduate Program in Neuroscience, University of Illinois at Chicago, 912 S. Wood Street, Chicago, IL 60612, USA. 2. Department of Orthopedics, University of Illinois at Chicago, 835 S. Wolcott Street, Chicago, IL 60612, USA. 3. Department of Neurology and Rehabilitation, Graduate Program in Neuroscience, University of Illinois at Chicago, 912 S. Wood Street, Chicago, IL 60612, USA. Electronic address: feisong@uic.edu. 4. Department of Neurology and Rehabilitation, Graduate Program in Neuroscience, University of Illinois at Chicago, 912 S. Wood Street, Chicago, IL 60612, USA. Electronic address: jaloeb@uic.edu.
Abstract
BACKGROUND: Amyotrophic lateral sclerosis (ALS) is poorly understood with no effective therapeutics. One long entertained observation is that ALS may be precipitated focally by nerve injury. Many patients with ALS are athletes or veterans, and some have suffered nerve injuries at the site where ALS first presents. Here we explore how a genetic SOD1 mutation alters the inflammatory response and affects functional recovery after an environmental insult in a rat model. METHODS: Unilateral sciatic nerve crush injuries were performed in SOD1 G93A rats prior to disease symptom onset. Functional recovery was compared between injured wild-type littermates and uninjured SOD1 rats. Spinal cord tissues were analyzed quantitatively for SOD1 expression, glial reactivity, and motor neuron synaptic integrity. RESULTS: Injured SOD1 rats failed to recover and showed hastened functional decline with decreased survival. Injury induced extracellular SOD1 expression was associated with heightened, prolonged microglial and astrogial activation in the ventral horn. This inflammatory response spread to uninjured motor neuron pools and was associated with increased motor neuron synaptic loss. DISCUSSION: This study identified a relationship between genetic and environmental contributions to disease onset and progression in ALS. The findings suggest that injury induced SOD1 mutant protein induces a heightened and prolonged inflammatory response resulting in motor neuron degeneration through synaptic loss. Once initiated, this process spreads to adjacent motor neurons leading to contiguous spread of the disease. Treatments that suppress this heightened glial response could slow disease progression in ALS patients with focal sites of disease onset. SIGNIFICANCE STATEMENT: The contribution of environmental factors such as peripheral nerve insults in ALS is not well understood. Here we examined the effect of a single sciatic nerve injury in SOD1 (G93A) rats to explore the contribution of this environmental insult on disease onset and progression. After the injury, SOD1 animals failed to recover and had a more rapid functional decline. Histopathologically, SOD1 animals had heightened SOD1 expression, microglial and astroglial responses, and a reduction of motor neuron innervation. Taken together, these results provide a plausible mechanism of how the SOD1 mutated protein promotes an abnormal response to injury that leads to neurodegenerative changes in an ALS model that is amenable to therapeutic testing.
BACKGROUND:Amyotrophic lateral sclerosis (ALS) is poorly understood with no effective therapeutics. One long entertained observation is that ALS may be precipitated focally by nerve injury. Many patients with ALS are athletes or veterans, and some have suffered nerve injuries at the site where ALS first presents. Here we explore how a genetic SOD1 mutation alters the inflammatory response and affects functional recovery after an environmental insult in a rat model. METHODS: Unilateral sciatic nerve crush injuries were performed in SOD1G93Arats prior to disease symptom onset. Functional recovery was compared between injured wild-type littermates and uninjured SOD1rats. Spinal cord tissues were analyzed quantitatively for SOD1 expression, glial reactivity, and motor neuron synaptic integrity. RESULTS: Injured SOD1rats failed to recover and showed hastened functional decline with decreased survival. Injury induced extracellular SOD1 expression was associated with heightened, prolonged microglial and astrogial activation in the ventral horn. This inflammatory response spread to uninjured motor neuron pools and was associated with increased motor neuron synaptic loss. DISCUSSION: This study identified a relationship between genetic and environmental contributions to disease onset and progression in ALS. The findings suggest that injury induced SOD1 mutant protein induces a heightened and prolonged inflammatory response resulting in motor neuron degeneration through synaptic loss. Once initiated, this process spreads to adjacent motor neurons leading to contiguous spread of the disease. Treatments that suppress this heightened glial response could slow disease progression in ALSpatients with focal sites of disease onset. SIGNIFICANCE STATEMENT: The contribution of environmental factors such as peripheral nerve insults in ALS is not well understood. Here we examined the effect of a single sciatic nerve injury in SOD1 (G93A) rats to explore the contribution of this environmental insult on disease onset and progression. After the injury, SOD1 animals failed to recover and had a more rapid functional decline. Histopathologically, SOD1 animals had heightened SOD1 expression, microglial and astroglial responses, and a reduction of motor neuron innervation. Taken together, these results provide a plausible mechanism of how the SOD1 mutated protein promotes an abnormal response to injury that leads to neurodegenerative changes in an ALS model that is amenable to therapeutic testing.
Authors: Zachary Osking; Jacob I Ayers; Ryan Hildebrandt; Kristen Skruber; Hilda Brown; Daniel Ryu; Amanda R Eukovich; Todd E Golde; David R Borchelt; Tracy-Ann Read; Eric A Vitriol Journal: iScience Date: 2019-08-16