Adreno-leukodystrophy: Oxidative Stress of Mice and Men
| Autor: | Ann B. Moser, Ann K. Heinzer, Hugo W. Moser, Paul A. Watkins, Kirby D. Smith, Rebecca Deering, James M. Powers, Zhengtong Pei |
|---|---|
| Rok vydání: | 2005 |
| Předmět: |
medicine.medical_specialty
Pathology Kidney Cortex Central nervous system Biology Mitochondrion medicine.disease_cause Biochemistry Pathology and Forensic Medicine Interferon-gamma Mice Cellular and Molecular Neuroscience Myelin chemistry.chemical_compound Internal medicine medicine Animals Humans Adrenoleukodystrophy Chemokine CCL22 Mice Knockout Superoxide Dismutase Adrenal cortex Leukodystrophy Brain General Medicine medicine.disease Malondialdehyde Immunohistochemistry Interleukin-12 Mitochondria Oxidative Stress Endocrinology medicine.anatomical_structure Liver Neurology chemistry Chemokines CC Knockout mouse Adrenal Cortex Tyrosine Neurology (clinical) Biomarkers Oxidative stress |
| Zdroj: | Journal of Neuropathology and Experimental Neurology. 64:1067-1079 |
| ISSN: | 0022-3069 |
| Popis: | X-linked adreno-leukodystrophy is a progressive, systemic peroxisomal disorder that affects primarily nervous system myelin and axons as well as the adrenal cortex. Several divergent clinical phenotypes can occur in the same family; thus, there is no correlation between the clinical phenotype and the mutation in the ABCD1 gene in this disease. The most urgent and unresolved clinical issue is the fulminant inflammatory (immune) demyelination of the central nervous system in which a variety of cellular participants, cytokines, and chemokines are noted. A knockout mouse model exhibits mitochondrial deficits and axonal degeneration, but not inflammatory demyelination. To determine whether oxidative stress and damage might play a pathogenic role, we assessed standard biochemical and immunohistochemical markers of such activity both in our knockout mouse model and patients. We find that oxidative stress, as judged by increased immunoreactivity for the mitochondrial manganese-superoxide dismutase, is present in the knockout mouse liver, adrenal cortex, and renal cortex, tissues that normally express high levels of ABCD1 but no evidence of oxidative damage. The brain does not exhibit either oxidative stress or damage. On the other hand, both the human adrenal cortex and brain show evidence of oxidative stress (e.g. hemoxygenase-1 and manganese-superoxide dismutase) and oxidative damage, particularly from lipid peroxidation (4-hydroxynonenal and malondialdehyde). The presence of nitrotyrosylated proteins is strong circumstantial evidence for the participation of the highly toxic peroxynitrite molecule, whereas the demonstration of interferon gamma and interleukin-12 is indicative of a TH1 response in the inflammatory demyelinative lesions of the cerebral phenotype. These differences between the adreno-leukodystrophy mouse and human patients are intriguing and may provide a clue to the phenotypic divergence in this disease. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|