title: Participation of autophagy in storage of lysosomes in neurons from mouse models of neuronal ceroid-lipofuscinoses (Batten disease).
abstract: In cathepsin D-deficient (CD-/-) and cathepsins B and L double-deficient (CB-/-CL-/-) mice, abnormal vacuolar structures accumulate in neurons of the brains. Many of these structures resemble autophagosomes in which part of the cytoplasm is retained but their precise nature and biogenesis remain unknown. We show here how autophagy contributes to the accumulation of these vacuolar structures in neurons deficient in cathepsin D or both cathepsins B and L by demonstrating an increased conversion of the molecular form of MAP1-LC3 for autophagosome formation from the cytosolic form (LC3-I) to the membrane-bound form (LC3-II). In both CD-/- and CB-/-CL-/- mouse brains, the membrane-bound LC3-II form predominated whereas MAP1-LC3 signals accumulated in granular structures located in neuronal perikarya and axons of these mutant brains and were localized to the membranes of autophagosomes, evidenced by immunofluorescence microscopy and freeze-fracture-replica immunoelectron microscopy. Moreover, as in CD-/- neurons, autofluorescence and subunit c of mitochondrial ATP synthase accumulated in CB-/-CL-/- neurons. This suggests that not only CD-/- but also CB-/-CL-/- mice could be useful animal models for neuronal ceroid-lipofuscinosis/Batten disease. These data strongly argue for a major involvement of autophagy in the pathogenesis of Batten disease/lysosomal storage disorders.
authors.affiliation: Department of Cell Biology and Neurosciences, Osaka University Graduate School of Medicine, Suita, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Koike
authors.forename: Masahiro
authors.initials: M
authors.lastname: Shibata
authors.forename: Satoshi
authors.initials: S
authors.lastname: Waguri
authors.forename: Kentaro
authors.initials: K
authors.lastname: Yoshimura
authors.forename: Isei
authors.initials: I
authors.lastname: Tanida
authors.forename: Eiki
authors.initials: E
authors.lastname: Kominami
authors.forename: Takahiro
authors.initials: T
authors.lastname: Gotow
authors.forename: Christoph
authors.initials: C
authors.lastname: Peters
authors.forename: Kurt
authors.initials: K
authors.lastname: von Figura
authors.forename: Noboru
authors.initials: N
authors.lastname: Mizushima
authors.forename: Paul
authors.initials: P
authors.lastname: Saftig
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Uchiyama
mesh_terms: D000818:Animals; D001343:Autophagy; D002401:Cathepsin B / Q000172:deficiency / Q000235:genetics; D002402:Cathepsin D / Q000172:deficiency / Q000235:genetics; D004195:Disease Models, Animal; D005614:Freeze Fracturing; D006580:Genetic Carrier Screening; D008247:Lysosomes / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D009472:Neuronal Ceroid-Lipofuscinoses / Q000235:genetics / Q000473:pathology*; D009474:Neurons / Q000473:pathology* / Q000648:ultrastructure; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D002401:Cathepsin B; D002402:Cathepsin D