Cathepsin D Deficiency Induces Lysosomal Storage with Ceroid Lipofuscin in Mouse CNS Neurons

Abstract

Cathepsin D-deficient (CDϪ/Ϫ) 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 biochemical features of CNS tissues of these mice. By electron microscopy, autophagosome/ autolysosome-like bodies containing part of the cytoplasm, granular osmiophilic deposits, and fingerprint profiles were demonstrated in the neuronal perikarya of CDϪ/Ϫ 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 region and the cerebral cortex, at P17. These lysosomal bodies occupied the perikarya of almost all neurons in CDϪ/Ϫ mouse brains obtained from P23 until the terminal stage. Because these neurons exhibited autofluorescence, it was considered that ceroid lipofuscin may accumulate in lysosomal structures of CDϪ/Ϫ neurons. Subunit c of mitochondrial ATP synthase was found to accumulate in the lysosomes of neurons, although the activity of tripeptidyl peptidase-I significantly increased in the brain. Moreover, neurons near the terminal stage were often shrunken and possessed irregular nuclei through which small dense chromatin masses were scattered. These results suggest that the CNS neurons in CDϪ/Ϫ mice show a new form of lysosomal accumulation disease with a phenotype resembling neuronal ceroid lipofuscinosis.

Regulation of MAP Kinases by the VHR Dual-Specific Phosphatase – Implications for Cell Growth and Differentiation

“…Some of these autolysosomes contained more condensed osmiophilic material, reminiscent of early lipofuscin granules, as seen for example in cathepsin D -/-mice. 110 As reported before in senescent cells, 111,112 the levels of CDK2, CDK4, and CDC2 decreased markedly. While it is possible that all these changes only reflect the accumulation of quiescent cells, they are similar to those that characterize the state of replicative senescence that untransformed cells enter after a defined number of cell division.…”

Overexpression of both catalytically active and -inactive cathepsin D by cancer cells enhances apoptosis-dependent chemo-sensitivity

“…Cath-D can either prevent apoptosis as described under physiological conditions with cath-D knockout mice experiments (Saftig et al, 1995;Koike et al, 2000Koike et al, , 2003Nakanishi et al, 2001), or can promote apoptosis induced by cytotoxic agents (Deiss et al, 1996;Roberg and Ö llinger, 1998;Wu et al, 1998;Ö llinger, 2000;Kagedal et al, 2001;Roberg, 2001;Johansson et al, 2003;Takuma et al, 2003;Emert-Sedlak et al, 2005). This duality in Catalytically active and -inactive cath-D induce mitochondrial release of cyt c and activation of caspases-9 and -3.…”

Neuronal loss and brain atrophy in mice lacking cathepsins B and L

“…Accumulation of ceroid-lipofuscinous material was observed in sheep with an enzymatically inactive form of the aspartic protease cathepsin D (33) and in mice with a truncated cathepsin D polypeptide (34,35). The accumulating inclusions in cathepsin B Ϫ/Ϫ ͞L Ϫ/Ϫ mice have a significantly earlier onset and a much more rapid progression resulting in apoptotic neuronal death and brain shrinkage not reported for cathepsin D-deficient mice.…”