Cathepsin D deficiency induces lysosomal storage with ceroid lipofuscin inmouse CNS neurons

Cathepsin D-deficient (CD-/-) mice have been shown to manifest seizures and become blind near the terminal stage [approximately postnatal day (P) 26]. We therefore examined the morphological, immunocytochemical, and biochemic al features of CNS tissues of these mice. By electron microscopy, autophago some/ autolysosome-like bodies containing part of the cytoplasm, granular o smiophilic deposits, and fingerprint profiles were demonstrated in the neur onal perikarya of CD-/- mouse brains after P20. Autophagosomes and granular osmiophilic deposits were detected in neurons at P0 but were few in number , whereas they increased in the neuronal perikarya within days after birth. Some large-sized neurons having autophagosome/ autolysosome-like bodies in the perikarya appeared in the CNS tissues, especially in the thalamic regi on and the cerebral cortex, at P17. These lysosomal bodies occupied the per ikarya of almost all neurons in CD-/- mouse brains obtained from P23 until the terminal stage. Because these neurons exhibited autofluorescence, it wa s considered that ceroid lipofuscin may accumulate in lysosomal structures of CD-/- neurons. Subunit c of mitochondrial ATP synthase was found to accu mulate in the lysosomes of neurons, although the activity of tripeptidyl pe ptidase-I significantly increased in the brain. Moreover, neurons near the terminal stage were often shrunken and possessed irregular nuclei through w hich small dense chromatin masses were scattered. These results suggest tha t the CNS neurons in CD-/- mice show a new form of lysosomal accumulation d isease with a phenotype resembling neuronal ceroid lipofuscinosis.