UBC Theses and Dissertations
An environmentally induced model of ALS-PDC and gene-environment interactions in neurological disease Wilson, Jason Murray Blair
The etiology of sporadic neurological diseases is unknown and the complete progression of the diseases remains undefined and poorly understood. Epidemiological studies have linked cycad flour consumption and the development of the neurodegenerative disorder, amyotrophic lateral sclerosis-parkinsonism dementia complex (ALS-PDC) of the Western Pacific. The presumed causal factor(s) is one or more of the toxins contained in washed cycad seed flour. In vivo studies of mice fed washed cycad seeds were tested with a battery of motor, cognitive, and olfactory behavioural measures that illustrated a temporal sequence of deficits correlated to neural cell death in the CNS. In addition, magnetic resonance microscopy (MRM) scans of the brains and spinal cords of cycad treated animals ex vivo showed decreased volumes in the CNS. Epidemiological data also suggest a correlation of ALS-PDC and particular susceptibility genes such as those coding for Apolipoprotein E (ApoE). Allele variations of ApoE have also been associated with genetic susceptibility to Alzheimer's disease, motor neuron diseases including ALS, and may affect the age of onset and disease progression. Initial experiments used both ApoE knock out (KO) mice and their wild-type (WT) counterparts to determine if the ApoE gene affected the level of cycad-induced neurodegeneration. Subsequently, washed cycad flour was fed to mice expressing the human ApoE alleles ApoE2, ApoE3, and ApoE4 and to WT mice. Cycad-fed WT mice developed progressive behavioural deficits including ALS-PDC-like pathological outcomes, while cycad-fed ApoE-KO mice were not significantly affected. Motor tests also revealed that all four groups of mice showed progressive motor deficits, with ApoE2 showing reduced deficits compared to ApoE4 and WT mice. ApoE2 mice also showed decreased pathology based on tyrosine hydroxylase labelling and motor neuron counts compared to other cycad-fed groups. Final studies were conducted to determine if an isolated cycad toxin fed to mice could induce an ALS-PDC phenotype. Mice were fed SG (β-sitosterol β-D-glucoside) as part of their normal diet for 10 weeks. Results showed that the SG feeding was toxic to motor neurons in the lumbar spinal cord. The insights gained from this model will be useful for future prophylaxis and treatment of human neurological diseases.
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