The role of attenuated astrocyte activation in infantile neuronal ceroid lipofuscinosis.
Infantile neuronal ceroid lipofuscinosis (INCL) is an inherited neurodegenerative disorder affecting the CNS during infancy. INCL is caused by mutations in the CLN1 gene that lead to a deficiency in the lysosomal hydrolase, palmitoyl protein thioesterase 1 (PPT1). A murine model of INCL, the PPT1-deficient (PPT1(-/-)) mouse, is an accurate phenocopy of the human disease. The first pathological change observed in the PPT1(-/-) brain is regional areas of glial fibrillary acidic protein (GFAP) upregulation, which predicts future areas of neurodegeneration. We hypothesized that preventing GFAP and vimentin upregulation in reactive astrocytes will alter the CNS disease. To test this hypothesis, we generated mice simultaneously carrying null mutations in the GFAP, Vimentin, and PPT1 genes (GFAP(-/-)Vimentin(-/-)PPT1(-/-)). Although the clinical and pathological features of the GFAP(-/-)Vimentin(-/-)PPT1(-/-) mice are similar to INCL, the disease appears earlier and progresses more rapidly. One mechanism underlying this accelerated phenotype is a profound neuroinflammatory response within the CNS. Thus, our data identify a protective role for intermediate filament upregulation during astrocyte activation in INCL, a model of chronic neurodegeneration.
Department of Internal Medicine and Genetics, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Shannon L
SL
Macauley
Milos
M
Pekny
Mark S
MS
Sands
D000704:Analysis of Variance; D000818:Animals; D001253:Astrocytes / Q000378:metabolism* / Q000473:pathology*; D001814:Blood-Testis Barrier / Q000503:physiopathology; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002199:Capillary Permeability / Q000235:genetics; D002540:Cerebral Cortex / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D005904:Glial Fibrillary Acidic Protein / Q000172:deficiency; D006801:Humans; D020244:Infarction, Middle Cerebral Artery / Q000150:complications; D007382:Intermediate Filaments / Q000235:genetics / Q000378:metabolism; D008136:Longevity / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009472:Neuronal Ceroid-Lipofuscinoses / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology*; D009929:Organ Size / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D016622:Silver Staining; D013869:Thiolester Hydrolases / Q000172:deficiency; D015854:Up-Regulation / Q000235:genetics*; D014746:Vimentin / Q000172:deficiency
D016207:Cytokines; D005904:Glial Fibrillary Acidic Protein; D012333:RNA, Messenger; D014746:Vimentin; D013869:Thiolester Hydrolases; C095299:palmitoyl-protein thioesterase