CNS-expressed cathepsin D prevents lymphopenia in a murine model of congenital neuronal ceroid lipofuscinosis.
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.
Shevtsova
Zinayida
Z
Department of Neurology, University Medicine Göttingen, Waldweg 33, 37073 Göttingen, Germany.
Garrido
Manuel
M
Weishaupt
Jochen
J
Saftig
Paul
P
Bähr
Mathias
M
Lühder
Fred
F
Kügler
Sebastian
S
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
D002566:Ceroid; D002402:Cathepsin D