Modeling the impact of H63D HFE polymorphism on amyotrophic lateral sclerosis (ALS)
Open Access
- Author:
- Nandar, Wint
- Graduate Program:
- Neuroscience
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- June 07, 2013
- Committee Members:
- James Robert Connor, Dissertation Advisor/Co-Advisor
James Robert Connor, Committee Chair/Co-Chair
Zachary Simmons, Committee Member
Robert Harold Bonneau, Committee Member
Patricia Grigson, Committee Member
Sang Yong Lee, Special Member - Keywords:
- H63D HFE
ALS
Iron
Oxidative stress
Gliosis
SOD1(G93A) - Abstract:
- Amyotrophic lateral sclerosis (ALS), commonly known as Lou Gehrig’s disease, is a progressive neurodegenerative disorder characterized by selective degeneration of upper and lower motor neurons in the brain and spinal cord. The etiology underlying or the genetic basis for the pathogenesis of sporadic ALS (sALS), which accounts for the majority of all cases, remains unclear. There is increasing evidence for an association between H63D HFE and ALS, with meta-analysis suggesting the presence of H63D HFE increases the risk of ALS 4-fold. Therefore, the main objective of this thesis is to evaluate the effect of H63D HFE on ALS pathogenesis. We generated two animal models to address our main objective. First, by generating a mouse model carrying H67D HFE (homologous to human H63D), we demonstrated that H67D HFE alters brain iron homeostasis and creates an environment for increased oxidative stress. The current paradigm relating to HFE gene variants holds that the blood-brain-barrier protects the brain from loss of iron homeostasis resulting from HFE mutations. Our findings provide direct in vivo evidence to challenge this paradigm and establish new models for neuroscience research. Second, by generating a double mutant mouse line (SOD1/H67D) carrying both H67D HFE and SOD1(G93A) mutation, I provided evidence that H63D HFE is a disease modifier for ALS. The presence of H67D HFE shortens survival and accelerates disease progression in the SOD1 transgenic mouse model of ALS (G93A). We identified mechanisms underlying this phenotype and demonstrated that elevated oxidative stress and increased gliosis associated with altered iron homeostasis contributes to accelerated disease in double mutant (SOD1/H67D) mice. Together, our studies suggest that H63D HFE is a genetic modifier for ALS independent of environmental factors and causes functional consequences in the brain and the spinal cord. These animal models can be used as a preclinical model to study how gene-environment interactions impact disease mechanisms and will aid in developing treatment strategies incorporating patient stratification by HFE genotype when assessing therapeutic interventions.