TNF-receptor 1 deficiency fails to alter the clinical and pathological course in mice with globoid cell leukodystrophy (twitcher mice) but affords protection following LPS challenge

• Published in: Journal of neuroimmunology Vol. 110; no. 1; pp. 186 - 194
• Main Authors: Pedchenko, Tetyana V., Bronshteyn, Illya G., LeVine, Steven M.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 02-10-2000
• Subjects: Animals; Blood-Brain Barrier - immunology; Brain - immunology; Brain - pathology; Demyelinating Diseases - genetics; Demyelinating Diseases - immunology; Demyelinating Diseases - pathology; Demyelination; Disease Models, Animal; Galactosylceramidase - genetics; Globoid cell leukodystrophy; Immune System - drug effects; Immune System - immunology; Krabbe’s disease; Leukodystrophy, Globoid Cell - genetics; Leukodystrophy, Globoid Cell - immunology; Leukodystrophy, Globoid Cell - pathology; Lipopolysaccharide; Lipopolysaccharides - pharmacology; Lysosomes - enzymology; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Neurologic Mutants; Oligodendroglia - immunology; Oligodendroglia - pathology; Organ Size; Receptors, Tumor Necrosis Factor - genetics; Receptors, Tumor Necrosis Factor - immunology; Sciatic Nerve - immunology; Sciatic Nerve - pathology; Tumor necrosis factor; tumor necrosis factor receptors; Lipopolysaccharide; Krabbe’s disease; Tumor necrosis factor; Demyelination; Globoid cell leukodystrophy
• ISSN: 0165-5728; 1872-8421
• DOI: 10.1016/S0165-5728(00)00345-3

Twitcher mice have an autosomal recessive mutation in the gene for the lysosomal enzyme galactosylceramidase, which is the same gene that is affected in human globoid cell leukodystrophy (Krabbe’s disease). The failure to digest galactosylceramide and psychosine leads to initial pathological changes in oligodendrocytes. Secondary pathological changes that include infiltrating macrophages and other inflammatory responses have been postulated to promote the disease course. TNFα levels are elevated in twitcher mice compared to control animals, and studies on another demyelinating disease, experimental allergic encephalomyelitis, indicate that TNF promotes pathogenesis via TNF-receptor 1 (TNF-R1). In the present study, twitcher/TNF-R1 deficient mice were generated, and the clinical and pathological course was compared between these mice and regular twitcher mice. There was no statistical evidence for any differences between these two groups of mice for all clinical (life span, weight loss, onset day of twitching) and pathological (demyelination, astrocyte gliosis, macrophage infiltration) measures that were examined. If mice were administered an intraperitoneal injection of LPS, then twitcher/TNF-R1 deficient mice had a shorter life span and an increased disruption to the blood–brain barrier compared to regular twitcher mice. These results showed that TNF-R1 is not sufficiently activated to affect the pathological and/or clinical signs during the natural course of this disease. However, when there is a secondary insult, TNF-R1 activation does lead to a significant acceleration of the development of clinical and pathological signs.