H63D HFE genotype accelerates disease progression in animal models of amyotrophic lateral sclerosis

Wint Nandar, Elizabeth B. Neely, Zachary Simmons, James Connor

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

H63D HFE is associated with iron dyshomeostasis and oxidative stress; each of which plays an important role in amyotrophic lateral sclerosis (ALS) pathogenesis. To examine the role of H63D HFE in ALS, we generated a double transgenic mouse line (SOD1/H67D) carrying the H67D HFE (homologue of human H63D) and SOD1(G93A) mutations. We found double transgenic mice have shorter survival and accelerated disease progression. We examined parameters in the lumbar spinal cord of double transgenic mice at 90. days (presymptomatic), 110. days (symptomatic) and end-stage. Transferrin receptor and L-ferritin expression, both indicators of iron status, were altered in double transgenic and SOD1 mice starting at 90. days, indicating loss of iron homeostasis in these mice. However, double transgenic mice had higher L-ferritin expression than SOD1 mice. Double transgenic mice exhibited increased Iba-1 immunoreactivity and caspase-3 levels, indicating increased microglial activation which would be consistent with the higher L-ferritin levels. Although both SOD1 and double transgenic mice had increased GFAP expression, the magnitude of the increase was higher in double transgenic mice at 110. days, suggesting increased gliosis in these mice. Increased hemeoxygenase-1 and decreased nuclear factor E2-related factor 2 levels in double transgenic mice strongly suggest the accelerated disease process could be associated with increased oxidative stress. There was no evidence of TAR-DNA-binding protein 43 mislocalization to the cytoplasm in double transgenic mice; however, there was evidence suggesting neurofilament disruption, which has been reported in ALS. Our findings indicate H63D HFE modifies ALS pathophysiology via pathways involving oxidative stress, gliosis and disruption of cellular functions.

Original languageEnglish (US)
Pages (from-to)2413-2426
Number of pages14
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1842
Issue number12
DOIs
StatePublished - Dec 1 2014

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Amyotrophic Lateral Sclerosis
Transgenic Mice
Disease Progression
Animal Models
Genotype
Apoferritins
Oxidative Stress
Gliosis
Iron
Spinal Cord
NF-E2-Related Factor 2
Heme Oxygenase-1
Transferrin Receptors
Intermediate Filaments
DNA-Binding Proteins
Caspase 3
Cytoplasm
Homeostasis
Mutation
Survival

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Molecular Biology

Cite this

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title = "H63D HFE genotype accelerates disease progression in animal models of amyotrophic lateral sclerosis",
abstract = "H63D HFE is associated with iron dyshomeostasis and oxidative stress; each of which plays an important role in amyotrophic lateral sclerosis (ALS) pathogenesis. To examine the role of H63D HFE in ALS, we generated a double transgenic mouse line (SOD1/H67D) carrying the H67D HFE (homologue of human H63D) and SOD1(G93A) mutations. We found double transgenic mice have shorter survival and accelerated disease progression. We examined parameters in the lumbar spinal cord of double transgenic mice at 90. days (presymptomatic), 110. days (symptomatic) and end-stage. Transferrin receptor and L-ferritin expression, both indicators of iron status, were altered in double transgenic and SOD1 mice starting at 90. days, indicating loss of iron homeostasis in these mice. However, double transgenic mice had higher L-ferritin expression than SOD1 mice. Double transgenic mice exhibited increased Iba-1 immunoreactivity and caspase-3 levels, indicating increased microglial activation which would be consistent with the higher L-ferritin levels. Although both SOD1 and double transgenic mice had increased GFAP expression, the magnitude of the increase was higher in double transgenic mice at 110. days, suggesting increased gliosis in these mice. Increased hemeoxygenase-1 and decreased nuclear factor E2-related factor 2 levels in double transgenic mice strongly suggest the accelerated disease process could be associated with increased oxidative stress. There was no evidence of TAR-DNA-binding protein 43 mislocalization to the cytoplasm in double transgenic mice; however, there was evidence suggesting neurofilament disruption, which has been reported in ALS. Our findings indicate H63D HFE modifies ALS pathophysiology via pathways involving oxidative stress, gliosis and disruption of cellular functions.",
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H63D HFE genotype accelerates disease progression in animal models of amyotrophic lateral sclerosis. / Nandar, Wint; Neely, Elizabeth B.; Simmons, Zachary; Connor, James.

In: Biochimica et Biophysica Acta - Molecular Basis of Disease, Vol. 1842, No. 12, 01.12.2014, p. 2413-2426.

Research output: Contribution to journalArticle

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