Author Koike M, Shibata M, Waguri S, Yoshimura K, Tanida I, Kominami E, Gotow T, Peters C, von Figura K, Mizushima N, Saftig P, Uchiyama Y.
Title Participation of autophagy in storage of lysosomes in neurons from mouse models of neuronal ceroid-lipofuscinoses (Batten disease).
Journal Am. J. Pathol.
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.
Volume 167(6)
Pages 1713-28
Published 2005-12
DOI 10.1016/S0002-9440(10)61253-9
PII S0002-9440(10)61253-9
PMID 16314482
PMC PMC1613187
MeSH Animals Autophagy Cathepsin B / deficiency Cathepsin B / genetics Cathepsin D / deficiency Cathepsin D / genetics Disease Models, Animal Freeze Fracturing Genetic Carrier Screening Lysosomes / pathology* Mice Mice, Knockout Neuronal Ceroid-Lipofuscinoses / genetics Neuronal Ceroid-Lipofuscinoses / pathology* Neurons / pathology* Neurons / ultrastructure Reverse Transcriptase Polymerase Chain Reaction
IF 4.069
Times Cited 211
Mice GFP-LC3#53 (RBRC00806)