Neuronal ceroid lipofuscinosis is one of many neurodegenerative storage diseases characterized by excessive accumulation of lipofuscins. CLN10 disease, an early
infantile neuronal ceroid lipofuscinosis, is associated with a gene that encodes
cathepsin D (CtsD), one of the major lysosomal
proteases. Whole body CtsD-knockout mice show neurodegenerative phenotypes with the accumulation of lipofuscins in the brain and also show defects in other tissues including intestinal
necrosis. To clarify the precise role of CtsD in the central nervous system (CNS), we generated a CNS-specific CtsD-knockout mouse (CtsD-CKO). CtsD-CKO mice were born normally but developed
seizures and their
growth stunted at around postnatal day 23 ± 1. CtsD-CKO did not exhibit apparent intestinal symptoms as those observed in whole body knockout. Histologically, autofluorescent materials were detected in several areas of the CtsD-CKO mouse's brain, including: thalamus, cerebral cortex, hippocampus, and cerebellum. Expression of
ubiquitin and autophagy-associated
proteins was also increased, suggesting that the autophagy-lysosome system was impaired. Microglia and astrocytes were activated in the CtsD-CKO thalamus, and
inducible nitric oxide synthase (iNOS), an
inflammation marker, was increased in the microglia. Interestingly, deposits of
proteinopathy-related
proteins, phosphorylated α-
synuclein, and
Tau protein were also increased in the thalamus of CtsD-CKO infant mice. Considering these results, we propose thatt the CtsD-CKO mouse is a useful mouse model to investigate the contribution of
cathepsin D to the early phases of
neurodegenerative diseases in relation to lipofuscins,
proteinopathy-related
proteins and activation of microglia and astrocytes.