title: Immune cells perturb axons and impair neuronal survival in a mouse model of infantile neuronal ceroid lipofuscinosis.
abstract: The neuronal ceroid lipofuscinoses are fatal neurodegenerative disorders in which the visual system is affected early in disease progression. A typical accompanying feature is neuroinflammation, the pathogenic impact of which is presently obscure. Here we investigated the role of inflammatory cells in palmitoyl protein thioesterase 1-deficient (Ppt1(-/-)) mice, a model of infantile neuronal ceroid lipofuscinosis (CLN1 disease, infantile), predominantly focusing on the visual system. We detected an early infiltration of CD8+ T-lymphocytes and observed activation of microglia/macrophage-like cells. To analyse the pathogenic impact of lymphocytes, we crossbred Ppt1(-/-) mice with mutants lacking lymphocytes (Rag1(-/-)), and scored axonal transport, axonal perturbation and neuronal survival. This lack of lymphocytes led to a significant amelioration of disease phenotypes, not only in the retino-tectal system, but also in other regions of the central nervous system. Finally, reconstitution experiments revealed a crucial role of CD8+ T-lymphocytes in pathogenesis. Our study provides novel pathomechanistic insights that may be crucial for developing treatment strategies.
authors.affiliation: Department of Neurology, Developmental Neurobiology, Josef-Schneider-Str. 11, D-97080 Wuerzburg, Germany. groh_J@klinik.uni-wuerzburg.de
authors.forename: Janos
authors.initials: J
authors.lastname: Groh
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Kühl
authors.forename: Chi Wang
authors.initials: CW
authors.lastname: Ip
authors.forename: Hemanth R
authors.initials: HR
authors.lastname: Nelvagal
authors.forename: Sarmi
authors.initials: S
authors.lastname: Sri
authors.forename: Steven
authors.initials: S
authors.lastname: Duckett
authors.forename: Myriam
authors.initials: M
authors.lastname: Mirza
authors.forename: Thomas
authors.initials: T
authors.lastname: Langmann
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Cooper
authors.forename: Rudolf
authors.initials: R
authors.lastname: Martini
mesh_terms: D000818:Animals; D001369:Axons / Q000276:immunology / Q000473:pathology*; D004195:Disease Models, Animal; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009472:Neuronal Ceroid-Lipofuscinoses / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D009474:Neurons / Q000276:immunology* / Q000473:pathology*; D010641:Phenotype; D013601:T-Lymphocytes; D013869:Thiolester Hydrolases / Q000172:deficiency / Q000235:genetics
chemical_list: D013869:Thiolester Hydrolases; C095299:palmitoyl-protein thioesterase