title: CNS-expressed cathepsin D prevents lymphopenia in a murine model of congenital neuronal ceroid lipofuscinosis.
abstract: Deficiency in Cathepsin D (CtsD), the major cellular lysosomal aspartic proteinase, causes the congenital form of neuronal ceroid lipofuscinoses (NCLs). CtsD-deficient mice show severe visceral lesions like lymphopenia in addition to their central nervous system (CNS) phenotype of ceroid accumulation, microglia activation, and seizures. Here we demonstrate that re-expression of CtsD within the CNS but not re-expression of CtsD in visceral organs prevented both central and visceral pathologies of CtsD(-/-) mice. Our results suggest that CtsD was substantially secreted from CNS neurons and drained from CNS to periphery via lymphatic routes. Through this drainage, CNS-expressed CtsD acts as an important modulator of immune system maintenance and peripheral tissue homeostasis. These effects depended on enzymatic activity and not on proposed functions of CtsD as an extracellular ligand. Our results furthermore demonstrate that the prominent accumulation of ceroid/lipofuscin and activation of microglia in brains of CtsD(-/-) are not lethal factors but can be tolerated by the rodent CNS.
authors.affiliation: Department of Neurology, University Medicine Göttingen, Waldweg 33, 37073 Göttingen, Germany.
authors.forename: Zinayida
authors.initials: Z
authors.lastname: Shevtsova
authors.forename: Manuel
authors.initials: M
authors.lastname: Garrido
authors.forename: Jochen
authors.initials: J
authors.lastname: Weishaupt
authors.forename: Paul
authors.initials: P
authors.lastname: Saftig
authors.forename: Mathias
authors.initials: M
authors.lastname: Bähr
authors.forename: Fred
authors.initials: F
authors.lastname: Lühder
authors.forename: Sebastian
authors.initials: S
authors.lastname: Kügler
mesh_terms: D000818:Animals; D002402:Cathepsin D / Q000235:genetics / Q000378:metabolism*; D002490:Central Nervous System / Q000378:metabolism* / Q000473:pathology; D002566:Ceroid / Q000378:metabolism; D000229:Dependovirus / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005822:Genetic Vectors; D006801:Humans; D008231:Lymphopenia / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism; D009472:Neuronal Ceroid-Lipofuscinoses / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000378:metabolism; D015996:Survival Rate; D013950:Thymus Gland / Q000166:cytology; D014018:Tissue Distribution; D014781:Viscera / Q000378:metabolism / Q000473:pathology
chemical_list: D002566:Ceroid; D002402:Cathepsin D