title: Increased activity and altered subcellular distribution of lysosomal enzymes determine neuronal vulnerability in Niemann-Pick type C1-deficient mice.
abstract: Niemann-Pick disease type C (NPC), caused by mutations in the Npc1 or Npc2 genes, is a progressive neurodegenerative disorder characterized by intracellular accumulation/redistribution of cholesterol in a number of tissues including the brain. This is accompanied by a severe loss of neurons in selected brain regions. In this study, we evaluated the role of lysosomal enzymes, cathepsins B and D, in determining neuronal vulnerability in NPC1-deficient (Npc1(-/-)) mouse brains. Our results showed that Npc1(-/-) mice exhibit an age-dependent degeneration of neurons in the cerebellum but not in the hippocampus. The cellular level/expression and activity of cathepsins B and D are increased more predominantly in the cerebellum than in the hippocampus of Npc1(-/-) mice. In addition, the cytosolic levels of cathepsins, cytochrome c, and Bax2 are higher in the cerebellum than in the hippocampus of Npc1(-/-) mice, suggesting a role for these enzymes in the degeneration of neurons. This suggestion is supported by our observation that degeneration of cultured cortical neurons treated with U18666A, which induces an NPC1-like phenotype at the cellular level, can be attenuated by inhibition of cathepsin B or D enzyme activity. These results suggest that the increased level/activity and altered subcellular distribution of cathepsins may be associated with the underlying cause of neuronal vulnerability in Npc1(-/-) brains. Therefore, their inhibitors may have therapeutic potential in attenuating NPC pathology.
authors.affiliation: Department of Psychiatry, Centre for Prions and Protein Folding Diseases, University of Alberta, Alberta, Canada.
authors.forename: Asha
authors.initials: A
authors.lastname: Amritraj
authors.forename: Kyle
authors.initials: K
authors.lastname: Peake
authors.forename: Anitha
authors.initials: A
authors.lastname: Kodam
authors.forename: Chiara
authors.initials: C
authors.lastname: Salio
authors.forename: Adalberto
authors.initials: A
authors.lastname: Merighi
authors.forename: Jean E
authors.initials: JE
authors.lastname: Vance
authors.forename: Satyabrata
authors.initials: S
authors.lastname: Kar
mesh_terms: D000818:Animals; D002401:Cathepsin B / Q000378:metabolism*; D002402:Cathepsin D / Q000378:metabolism*; D002531:Cerebellum / Q000378:metabolism / Q000473:pathology; D002784:Cholesterol / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D015151:Immunoblotting; D047908:Intracellular Signaling Peptides and Proteins; D008247:Lysosomes / Q000201:enzymology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D009410:Nerve Degeneration / Q000201:enzymology* / Q000473:pathology; D009474:Neurons / Q000201:enzymology / Q000473:pathology; D000077296:Niemann-Pick C1 Protein; D052556:Niemann-Pick Disease, Type C / Q000201:enzymology* / Q000473:pathology; D011506:Proteins / Q000235:genetics*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D000077296:Niemann-Pick C1 Protein; C106831:Npc1 protein, mouse; D011506:Proteins; D002784:Cholesterol; D002401:Cathepsin B; D002402:Cathepsin D