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An environmentally induced model of ALS-PDC and gene-environment interactions in neurological disease Wilson, Jason Murray Blair
Abstract
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.
Item Metadata
Title |
An environmentally induced model of ALS-PDC and gene-environment interactions in neurological disease
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Creator | |
Publisher |
University of British Columbia
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Date Issued |
2005
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Description |
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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Genre | |
Type | |
Language |
eng
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Date Available |
2009-12-23
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Provider |
Vancouver : University of British Columbia Library
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Rights |
For non-commercial purposes only, such as research, private study and education. Additional conditions apply, see Terms of Use https://open.library.ubc.ca/terms_of_use.
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DOI |
10.14288/1.0092371
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URI | |
Degree | |
Program | |
Affiliation | |
Degree Grantor |
University of British Columbia
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Graduation Date |
2005-11
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Campus | |
Scholarly Level |
Graduate
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Aggregated Source Repository |
DSpace
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Item Media
Item Citations and Data
Rights
For non-commercial purposes only, such as research, private study and education. Additional conditions apply, see Terms of Use https://open.library.ubc.ca/terms_of_use.