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(American Journal of Pathology. 2005;167:1713-1728.)
© 2005 American Society for Investigative Pathology

Participation of Autophagy in Storage of Lysosomes in Neurons from Mouse Models of Neuronal Ceroid-Lipofuscinoses (Batten Disease)

Masato Koike^*, Masahiro Shibata^*, Satoshi Waguri^*, Kentaro Yoshimura^*, Isei Tanida, Eiki Kominami, Takahiro Gotow, Christoph Peters, Kurt von Figura^¶, Noboru Mizushima^||, Paul Saftig^** and Yasuo Uchiyama^*

From the Department of Cell Biology and Neurosciences,^* Osaka University Graduate School of Medicine, Osaka, Japan; the Department of Biochemistry, Juntendo University School of Medicine, Tokyo, Japan; the Laboratory of Cell Biology, College of Nutrition, Koshien University, Hyogo, Japan; the Department of Bioregulation and Metabolism,|| Tokyo Metropolitan Institute of Medical Sciences, Tokyo, Japan; the Institut für Molekuläre Medizin und Zellforschung, Albert Ludwigs Universität Freibrug, Freibrug, Germany; the Center for Biochemistry and Molecular Cell Biology, ^¶ Göttingen University, Göttingen, Germany; and the Department of Biochemistry,^** University Kiel, Kiel, Germany

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.

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