Increase in cathepsin D activity in rat brain in aging

Kenessey, Ágnes; Banay‐Schwartz, M.; DeGuzman, T.; Lajtha, Ábel

doi:10.1002/jnr.490230412

Cited by 61 publications

(30 citation statements)

References 18 publications

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“…Increased concentrations and activities of cathepsin D also occur in both conditions (Kenessey et al, 1989;Nakanishi et al, 1994;Cataldo et al, 1995), and there is also evidence that these increases are accompanied by leakage of the protease into the cytoplasm (Nakamura et al, 1989). A tau protein fragment similar in size to that generated when tau is exposed to cathepsin D is found in neurofibrillary tangles (Nieto et al, 1990; for discussion, see also Bednarski and Lynch, 1996).…”

Section: Discussionmentioning

confidence: 98%

Suppression of Cathepsins B and L Causes a Proliferation of Lysosomes and the Formation of Meganeurites in Hippocampus

Bednarski¹,

Ribak

Lynch³

1997

J. Neurosci.

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Cultured hippocampal slices exhibited prominent ultrastructural features of brain aging after exposure to an inhibitor of cathepsins B and L. Six days of treatment with N-CBZ-Lphenylalanyl-L-alanine-diazomethylketone (ZPAD) resulted in a dramatic increase in the number of lysosomes in the perikarya of neurons and glial cells throughout the slices. Furthermore, lysosomes in CA1 and CA3 pyramidal cells were not restricted to the soma but instead were located throughout dendritic processes. Clusters of lysosomes were commonly found within bulging segments of proximal dendrites that were notable for an absence of microtubules and neurofilaments. Although pyknotic nuclei were sometimes encountered, most of the cells in slices exposed to ZPAD for 6 d appeared relatively normal. Slices given 7 d of recovery contained several unique features, compared with those processed immediately after incubation with the inhibitor. Cell bodies of CA1 neurons were largely cleared of the excess lysosomes but had gained fusiform, somatic extensions that were filled with fused lysosomes and related complex, dense bodies. These appendages, similar in form and content to structures previously referred to as "meganeurites," were not observed in CA3 neurons or granule cells. Because meganeurites were often interposed between cell body and axon, they have the potential to interfere with processes requiring axonal transport. It is suggested that inactivation of cathepsins B and L results in a proliferation of lysosomes and that meganeurite generation provides a means of storing residual catabolic organelles. The accumulated material could be eliminated by pinching off the meganeurite but, at least in some cases, this action would result in axotomy. Reduced cathepsin L activity, increased numbers of lysosomes, and the formation of meganeurites are all reported to occur during brain aging; thus, it is possible that the infusion of ZPAD into cultured slices sets in motion a greatly accelerated gerontological sequence.

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Section: Discussionmentioning

confidence: 98%

Suppression of Cathepsins B and L Causes a Proliferation of Lysosomes and the Formation of Meganeurites in Hippocampus

Bednarski¹,

Ribak

Lynch³

1997

J. Neurosci.

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“…In the rat brain, cathepsin D was detected in both neurons and glial cells. Increased cathepsin D has been reported in aging, [9][10][11] Alzheimer's disease, 12,13) and dystrophy 14) ; however, the physiological and pathological significance is poorly understood. In addition, the mechanism of cathepsin D accumulation in cytosol in the aging process remains elusive.…”

mentioning

confidence: 99%

Translocation of Lysosomal Cathepsin D Caused by Oxidative Stress or Proteasome Inhibition in Primary Cultured Neurons and Astrocytes

Miura

Sakurai

Hayakawa

et al. 2010

Biological & Pharmaceutical Bulletin

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Proteins produced by eukaryotic cells frequently undergo various post-translational modifications, such as phosphorylation, acetylation, ubiquitination, and glycosylation. The modified proteins perform various functions involved in signal transduction, localization, and degradation signals. Among them, glycosylation is the most common protein modification in mammals.2) In the biosynthesis of N-linked glycoprotein, sugar chains are added to nascent polypeptides and processed by various enzymes in the endoplasmic reticulum and Golgi apparatus, and the complete glycoproteins are transported to their target organelles or secreted extracellularly by means of vesicular traffic. Therefore, with some exceptions, 3) N-linked glycoproteins can not be found in the cytosol [4][5][6] ; however, we have reported the accumulation of N-glycoproteins in the cytosol in both Alzheimer's disease 7) and normal aging of the rat brain. 8) In a normally aging rat brain, accumulated N-glycoproteins were detected by two-dimensional polyacrylamide gel electrophoresis and lectin blot, and one protein was identified as cathepsin D, a lysosomal protease.8) Cathepsin D is a major intracellular aspartic protease. In the rat brain, cathepsin D was detected in both neurons and glial cells. Increased cathepsin D has been reported in aging, 9-11) Alzheimer's disease, 12,13) and dystrophy 14) ; however, the physiological and pathological significance is poorly understood. In addition, the mechanism of cathepsin D accumulation in cytosol in the aging process remains elusive. 8)Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are constantly produced in various cells and tissues. The concentrations of these reactive species are determined by redox balance between the rates of production from endogenous and exogenous origins and the rates of clearance by various antioxidant systems; however, the redox balance gradually degenerates with aging, finally resulting in oxidative stress, 15,16) which is thought to cause the dysfunction of various subcellular components, including lysosomes.This suggests that oxidative stress may induce changes in the intracellular distribution of cathepsin D.The accumulation of cathepsin D in the cytosol may be also induced by the dysfunction of protein degradation systems. Protein degradation systems are categorized into lysosomal and non-lysosomal systems, such as proteasomes. Proteasome protein degradation is known to eliminate misfolded/unassembled (glyco)proteins in the cytosol; therefore, the decline of proteasome activity may lead to the accumulation of cathepsin D in the cytosol.It is important to elucidate the mechanism of cathepsin D accumulation in the cytosol of the rat brain during aging; however, it is difficult to examine the whole brain because it is too complicated. Therefore, we used primary cultured neurons and astrocytes derived from the brain, and examined whether oxidative stress and proteasome inhibition induced the accumulation of cathepsin D in the cytosol and also induced apoptosis...

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“…Interest in cathepsin D as a target for drug design results from its association with several biological processes of therapeutic significance including lysosomal biogenesis and protein targeting (4,5), antigen processing and the presentation of peptide fragments to class II major histocompatibility complexes (8)(9)(10), connective tissue disease pathology (11), muscular dystrophy (12), degenerative brain changes (13,14), and cleavage of amyloid precursor protein within senile plaques of Alzheimer brain (15). Recent studies of primary breast cancers demonstrated that elevated levels of cathepsin D were correlated with an increased risk of metastasis and shorter relapse-free survival (16).…”

mentioning

confidence: 99%

Crystal structures of native and inhibited forms of human cathepsin D: implications for lysosomal targeting and drug design.

Baldwin

Bhat²,

Gulnik³

et al. 1993

Proc. Natl. Acad. Sci. U.S.A.

260

208

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Cathepsin D (EC 3.4.23.5) is a lysosomal protease suspected to play important roles in protein catabolism, antigen processing, degenerative diseases, and breast cancer progresson. Determination of the crystal structures of cathepsin D and a complex with pepstatin at 2.5 A resolution provides insights into inhibitor binding and lysosomal targeting for this two-chain, N-glycosylated aspartic protease. Comparison with the structures of a complex of pepstatin bound to rhizopuspepsin and with a human renin-bihbitor complex revealed differences in subsite structures and inhibitor-enzyme interactions that are consistent with affnity differences and structure-activity relationships and suggest strategies for fmetuning the specificity of cathepsin D inhibitors. Mutagenesis studies have identified a phosphotransferase recognition region that is required for oligosaccharide phosphorylation but is 32 A distant from the N-domain glycosylation site at Asn-70. Electron density for the crystal structure of cathepsin D indicated the presence of an N-linked oligosaccharide that extends from Asn-70 toward Lys-203, which is a key component of the phosphotransferase recognition region, and thus provides a structural explanation for how the phosphotransferase can recognize apparently distnt sites on the protein surface.Cathepsin D (EC 3.4.23.5) is an aspartic protease that is normally found in the lysosomes of higher eukaryotes where it functions in protein catabolism (1). This enzyme is distinguished from other members of the pepsin family (2) by two features that are characteristic of lysosomal hydrolases. First, mature cathepsin D is found predominantly in a twochain form due to a posttranslational cleavage event (1, 3). Second, it contains phosphorylated, N-linked oligosaccharides that target the enzyme to lysosomes via mannose 6-phosphate (M6P) receptors (4, 5). Phosphorylation involves recognition of both sugar and protein structural determinants by a phosphotransferase enzyme (6, 7).Interest in cathepsin D as a target for drug design results from its association with several biological processes of therapeutic significance including lysosomal biogenesis and protein targeting (4,5), antigen processing and the presentation of peptide fragments to class II major histocompatibility complexes (8-10), connective tissue disease pathology (11), muscular dystrophy (12), degenerative brain changes (13,14), and cleavage of amyloid precursor protein within senile plaques of Alzheimer brain (15). Recent duced in the vicinity of the growing tumor, may degrade the extracellular matrix and thereby promote the escape of cancer cells to the lymphatic and circulatory systems and enhance the invasion of new tissues (17,18). The design of potent and specific inhibitors of cathepsin D will aid the further elucidation of the roles of this enzyme in human disease. We previously described the purification and crystallization ofhuman cathepsin D from liver (3); similar studies have been reported recently for cathepsin D isolated from bovine l...

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Increase in cathepsin D activity in rat brain in aging

Cited by 61 publications

References 18 publications

Suppression of Cathepsins B and L Causes a Proliferation of Lysosomes and the Formation of Meganeurites in Hippocampus

Suppression of Cathepsins B and L Causes a Proliferation of Lysosomes and the Formation of Meganeurites in Hippocampus

Translocation of Lysosomal Cathepsin D Caused by Oxidative Stress or Proteasome Inhibition in Primary Cultured Neurons and Astrocytes

Crystal structures of native and inhibited forms of human cathepsin D: implications for lysosomal targeting and drug design.

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