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

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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.

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Supported by the Brain Mapping by Integrated Neurotechnologies for Disease Studies (Brain/MINDS) from Japan Agency for Medical Research and Development AMED (M.K.), Scientific Research on Innovative Areas grants 23111004 (Y.U.) and 26111519 and 15H01388 (M.K.), Scientific Research (B) grant-in-aid 23390041 (Y.U.), Scientific Research (C) grant-in-aid 25460276 (M.K.), Challenging Exploratory Research grant-in-aid 25670099 (Y.U.), a grant-in-aid for the High-Tech Research Center Project for Private Universities, a matching fund subsidy (Y.U.), the Program for the Strategic Research Foundation at Private Universities (Y.U.), the Private University Research Branding Project (M.K.) from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and the Nagao Takeshi Nanbyo Foundation (M.K.).

Disclosures: None declared.