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Am J Pathol. 2017 Jul;187(7):1586-1600. doi: 10.1016/j.ajpath.2017.02.020. Epub 2017 May 11.

Purkinje Cells Are More Vulnerable to the Specific Depletion of Cathepsin D Than to That of Atg7.

Author information

1
Department of Cell Biology and Neuroscience, Juntendo University Graduate School of Medicine, Bunkyo-ku, Tokyo, Japan.
2
Department of Morphological Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
3
Department of Cell Biology and Neuroscience, Juntendo University Graduate School of Medicine, Bunkyo-ku, Tokyo, Japan; Department of Cellular and Molecular Neuropathology, Juntendo University Graduate School of Medicine, Bunkyo-ku, Tokyo, Japan.
4
Department of Cellular and Molecular Neuropathology, Juntendo University Graduate School of Medicine, Bunkyo-ku, Tokyo, Japan.
5
Department of Cellular Neurobiology, Brain Research Institute, Niigata University, Niigata, Japan.
6
Department of Molecular Genetics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
7
Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, Setagaya-Ku, Tokyo, Japan.
8
Department of Cellular and Molecular Neuropathology, Juntendo University Graduate School of Medicine, Bunkyo-ku, Tokyo, Japan. Electronic address: y-uchi@juntendo.ac.jp.

Abstract

Neurologic phenotypes of cathepsin D (CTSD)-deficient mice, a murine model of neuronal ceroid lipofuscinoses, indicate the importance of CTSD for the maintenance of metabolism in central nervous system neurons. To further understand the role of CTSD in central nervous system neurons, we generated mice with a CTSD deficiency specifically in the Purkinje cells (PCs) (CTSDFlox/Flox;GRID2-Cre) and compared their phenotypes with those of PC-selective Atg7-deficient (Atg7Flox/Flox;GRID2-Cre) mice. In both strains of mice, PCs underwent degeneration, but the CTSD-deficient PCs disappeared more rapidly than their Atg7-deficient counterparts. When CTSD-deficient PCs died, the neuronal cell bodies became shrunken, filled with autophagosomes and autolysosomes, and had nuclei with dispersed small chromatin fragments. The dying Atg7-deficient PCs also showed similar ultrastructures, indicating that the neuronal cell death of CTSD- and Atg7-deficient PCs was distinct from apoptosis. Immunohistochemical observations showed the formation of calbindin-positive axonal spheroids and the swelling of vesicular GABA transporter-positive presynaptic terminals that were more pronounced in Atg7-deficient PCs than in CTSD-deficient PCs. An accumulation of tubular vesicles may have derived from the smooth endoplasmic reticulum; nascent autophagosome-like structures with double membranes was a common feature in the swollen axons of these PCs. These results suggested that PCs were more vulnerable to CTSD deficiency in lysosomes than to autophagy impairment, and this vulnerability does not depend on the severity of axonal swelling.

PMID:
28502476
DOI:
10.1016/j.ajpath.2017.02.020
[Indexed for MEDLINE]

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