Christopher Shaw
Relevant Thesis-Based Degree Programs
Graduate Student Supervision
Doctoral Student Supervision
Dissertations completed in 2010 or later are listed below. Please note that there is a 6-12 month delay to add the latest dissertations.
The majority of ALS patients have a sporadic form of ALS (sALS), which lack evidence of a dominantly inherited genetic factor. sALS has long been associated with environmental factors such as toxicants, however a clear causal relationship between the environment and sALS has yet to be demonstrated. It is likely that susceptibility genes predispose individuals to develop sALS, and advances in genetics are now identifying sALS risk genes. The majority of single nucleotide polymorphisms (SNPs) are located in non-coding DNA, and the effort to understand the genetic basis of disease is shifting to focus on non-coding regions. Enhancer regulatory elements (eREs) are a type of regulatory element located in non-coding DNA that function to increase gene expression. However, the role of eREs in ALS remains unknown. Here I investigated if toxicants and/or genetic components can be considered as sALS risk factors. The overall hypothesis of my work is that variants in gene enhancer elements are sALS risk factors, which interact with environmental toxicants to drive motor neuron degeneration. I described the effect of lead (Pb) on motor neuron degeneration and further studied the pathogenesis underlying toxicant-induced degeneration. To screen low frequency variants for eREs, I used sALS summary statistics from a large genome wide association study and identified SNPs in 312 distinct eREs. I further prioritized 13 top candidate eRE target genes using RNA-seq data from laser captured motor neurons from sALS patients. Through functional analysis, I demonstrated that knockdown of nucleoporin 50 (nup50), a component of nuclear pore complex, in vivo in a zebrafish model results in motor neuron degeneration, proposing 4 eREs targeting NUP50 as novel sALS risk factors. Further, I investigated the effect of gene-toxicant interactions and demonstrated the synergistic effects on toxicity despite a lacking motor phenotype. These findings describe pathogenic features underlying toxicant-induced motor neuron degeneration, demonstrate a role of eREs as novel sALS risk factors and highlight the complicated nature of modeling gene-toxicant interactions.
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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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Master's Student Supervision
Theses completed in 2010 or later are listed below. Please note that there is a 6-12 month delay to add the latest theses.
Amyotrophic lateral sclerosis is a fatally progressive neurodegenerative disease characterized by the loss of motor neurons in both the brain and spinal cord. Neuronal cell death leads to a lack of muscle innervation which eventually gives rise to paralysis. Patients typically survive less than five years following the initial onset; with respiratory complications ultimately causal in death. The majority of ALS cases are of unknown etiology, with around 5% linked to aberrant genetic mutations. The most well characterized mutations account for approximately 1-2% of all ALS cases, and are linked to the genetic locus for superoxide dismutase-1 (SOD1). The severity of disease and the concomitant lack of effective therapeutic options necessitate significant research efforts in search of viable treatment options that would significantly impede and/or reverse the ultimate loss of motor neurons. Progranulin (PGRN) may be one such an option since the protein is a secreted growth factor that has demonstrated neuroprotective outcomes in models of Alzheimer’s- and Parkinson’s disease and may generally be important in the long term survival of neurons. Employing a lentiviral-mediated delivery mechanism at a stage prior to disease onset, we set out to assess the potential neurotrophic properties of exogenously delivered PGRN cDNA when targeted to neuronal subsets within the lumbar spinal cord of mice expressing mutant SOD1. The resultant outcomes at both the behavioural and neuropathological levels did not demonstrate any significant protective effect from the lentiviral delivery of exogenous PGRN. PGRN-treated cohorts did not exhibit an increase in overall survival, a decrease in gliosis, or an increase in neuronal viability when compared to the GFP-lentiviral-injected control groups. This study suggests that PGRN delivery at an early stage of ALS neurodegeneration preceding the phenotypic expression of disease may not be a viable therapeutic option in ameliorating the ALS degenerative cascade. Technical caveats to this interpretation are discussed. One of these includes the unexpected reduction in the copy number of the mSOD1 gene in transgenic mice, which ultimately presenting with a protracted progression of the disease. The present study thus additionally underscores some of the challenges faced in pre-clinical therapeutic development using murine ALS models.
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