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Determination of disease progression with early toxin-induced neuropathology in the ageing mutant SOD mouse model of amyotrophic lateral sclerosis Kam, Grace Lee

Abstract

Adult onset amyotrophic lateral sclerosis (ALS) poses progressive and irreversible functional deficits to the central nervous system due to loss of motor neurons, caused by some poorly characterized, multifactorial etiology. Research focused on sporadic ALS cases with vastly greater incidence than hereditary ALS describes the potential causes to be of environmental origin. The discovery of endemic ALS in the native Chamorro population of Guam during the 1950s and the co-occurence of Parkinsonism and dementia led to searches for an environmental cause. To determine whether a genetic predisposition to adult-onset ALS could be exacerbated by a toxin that is known to produce a similar phenotype, I combined genetic and environmental models of ALS and tested a known neurotoxin (steryl glucosides) for its potential synergistic properties in combination with the genetic defect. Transgenic SOD1 G37R mice were treated with 42 mg toxin per kilogram of body weight daily in their daily diet. Results showed an additive effect of toxinonspinal motor neuron death, and caused decreases in average soma diameter on surviving motor neurons. The presence of the transgene alone resulted in smaller diameter ventral root axons.Toxin exposure alone resulted in a bimodal configuration of the ventral root size histogram resembling a more immature state of motor axons.The transgene alone markedly increased the amount of GFAP- and Iba1-positive glial cells in the spinal cord grey matter, with a heterogeneous expression of ramified (resting) and activated morphology. The transgene in combination with toxin did not significantly change glial numbers, but caused all glial cells to become extensively activated. Although the mechanism of cycad toxin-induced neurodegeneration remains uncertain, these results showed that dietary exposure to environmental toxin alone was sufficient to produce a disease phenotype, and when implemented in conjunction to a genetic predisposition to ALS was sufficient to produce a more severe disease phenotype. In conclusion, the environmental agent studied here has direct cytotoxic effects, contributes to disease progression in ALS, and indicate an additive effect of dietary neurotoxin in combination with genetic mutations leading to familial ALS.

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