Investigating the interplay of intrinsic to extrinsic factors influencing amyotrophic lateral sclerosis disease progression
Open Access
- Author:
- Su, Xiaowei William
- Graduate Program:
- Molecular Medicine
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- June 17, 2014
- Committee Members:
- James Robert Connor, Dissertation Advisor/Co-Advisor
Xuemei Huang, Committee Member
Zachary Simmons, Committee Member
Hanspeter Waldner, Committee Member - Keywords:
- amyotrophic lateral sclerosis
H63D HFE
biomarker
ferritin
HMG-CoA reductase inhibitor - Abstract:
- Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder affecting motor neurons in the spinal cord, brainstem and motor cortex. The disease induces paralysis, and death results from respiratory failure. The pathogenesis of ALS begins before a diagnosis can be made in the clinic. Analyzing processes influencing disease progression is an important strategy to elucidate disease mechanisms. We investigated factors influencing ALS disease progression, using the framework that the interplay of a range of extrinsic and intrinsic factors determine phenotypes. Our analysis of intrinsic, genetic factors focused on the H63D polymorphism in the HFE iron regulatory gene. Our results suggest homozygosity for H63D HFE is correlated with approximately 2-year longer disease duration and decreased levels of soluble superoxide dismutase protein in patients with ALS. We propose H63D HFE causes mild endoplasmic reticulum stress, which increases the risk for ALS but also promotes adaptive mechanisms that prolong survival in those who develop ALS. Studies analyzing intermediate factors focused on protein biomarkers. We measured 35 biomarkers in cerebrospinal fluid and plasma of patients with ALS, and created models predicting ALS prognosis based on biomarkers panels comprised of inflammatory cytokines, growth factors, and iron metabolism markers. We then focused on ferritin, which correlated with longer disease duration in our models. Our results suggest ferritin is elevated in the blood of patients with ALS versus healthy controls and those with non-ALS neurological diseases. We propose elevated ferritin in ALS patients is an adaptive response to oxidative damage. Studies analyzing extrinsic factors focused on pharmacotherapies. Our results suggest HMG-CoA reductase inhibitors (statins), which are commonly prescribed to manage cholesterol, adversely impact phenotype in ALS model mice. G93A SOD1 mice administered statins had accelerated disease progression and decreased survival, with double transgenic animals harboring both SOD1 G93A and H67D HFE, homologous to human H63D HFE, having the worst phenotype. This underscores the need for surveillance of disease progression in patients with ALS receiving statin therapy. Our results suggest strategies to stratify patients in clinical trials, enabling more precise evaluation of outcomes; as well as therapeutic approaches that may improve the clinical situation for patients with ALS.