title: Cathepsin D deficiency induces lysosomal storage with ceroid lipofuscin in mouse CNS neurons.
abstract: Cathepsin D-deficient (CD-/-) mice have been shown to manifest seizures and become blind near the terminal stage [approximately postnatal day (P) 26]. We therefore examined the morphological, immunocytochemical, and biochemical features of CNS tissues of these mice. By electron microscopy, autophagosome/autolysosome-like bodies containing part of the cytoplasm, granular osmiophilic deposits, and fingerprint profiles were demonstrated in the neuronal perikarya of CD-/- mouse brains after P20. Autophagosomes and granular osmiophilic deposits were detected in neurons at P0 but were few in number, whereas they increased in the neuronal perikarya within days after birth. Some large-sized neurons having autophagosome/autolysosome-like bodies in the perikarya appeared in the CNS tissues, especially in the thalamic region and the cerebral cortex, at P17. These lysosomal bodies occupied the perikarya of almost all neurons in CD-/- mouse brains obtained from P23 until the terminal stage. Because these neurons exhibited autofluorescence, it was considered that ceroid lipofuscin may accumulate in lysosomal structures of CD-/- neurons. Subunit c of mitochondrial ATP synthase was found to accumulate in the lysosomes of neurons, although the activity of tripeptidyl peptidase-I significantly increased in the brain. Moreover, neurons near the terminal stage were often shrunken and possessed irregular nuclei through which small dense chromatin masses were scattered. These results suggest that the CNS neurons in CD-/- mice show a new form of lysosomal accumulation disease with a phenotype resembling neuronal ceroid lipofuscinosis.
authors.affiliation: Department of Cell Biology and Neurosciences, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Koike
authors.forename: H
authors.initials: H
authors.lastname: Nakanishi
authors.forename: P
authors.initials: P
authors.lastname: Saftig
authors.forename: J
authors.initials: J
authors.lastname: Ezaki
authors.forename: K
authors.initials: K
authors.lastname: Isahara
authors.forename: Y
authors.initials: Y
authors.lastname: Ohsawa
authors.forename: W
authors.initials: W
authors.lastname: Schulz-Schaeffer
authors.forename: T
authors.initials: T
authors.lastname: Watanabe
authors.forename: S
authors.initials: S
authors.lastname: Waguri
authors.forename: S
authors.initials: S
authors.lastname: Kametaka
authors.forename: M
authors.initials: M
authors.lastname: Shibata
authors.forename: K
authors.initials: K
authors.lastname: Yamamoto
authors.forename: E
authors.initials: E
authors.lastname: Kominami
authors.forename: C
authors.initials: C
authors.lastname: Peters
authors.forename: K
authors.initials: K
authors.lastname: von Figura
authors.forename: Y
authors.initials: Y
authors.lastname: Uchiyama
mesh_terms: D000200:Action Potentials / Q000235:genetics; D000818:Animals; D001766:Blindness / Q000209:etiology; D002401:Cathepsin B / Q000378:metabolism; D002402:Cathepsin D / Q000172:deficiency* / Q000235:genetics; D002490:Central Nervous System / Q000201:enzymology* / Q000473:pathology / Q000648:ultrastructure; D006624:Hippocampus / Q000473:pathology / Q000502:physiology; D006720:Homozygote; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D020140:Lysosomal Storage Diseases, Nervous System / Q000201:enzymology* / Q000235:genetics; D008247:Lysosomes / Q000201:enzymology / Q000235:genetics / Q000648:ultrastructure; D051379:Mice; D018345:Mice, Knockout; D025261:Mitochondrial Proton-Translocating ATPases; D009472:Neuronal Ceroid-Lipofuscinoses / Q000201:enzymology* / Q000235:genetics; D009474:Neurons / Q000201:enzymology* / Q000473:pathology / Q000648:ultrastructure; D010588:Phagosomes / Q000235:genetics / Q000648:ultrastructure; D010641:Phenotype; D006180:Proton-Translocating ATPases / Q000378:metabolism; D012640:Seizures / Q000209:etiology; D000091346:Tripeptidyl-Peptidase 1
chemical_list: C000717268:Tpp1 protein, mouse; D000091346:Tripeptidyl-Peptidase 1; D002401:Cathepsin B; D002402:Cathepsin D; C103607:mitochondrial ATPase subunit c; D025261:Mitochondrial Proton-Translocating ATPases; D006180:Proton-Translocating ATPases