In vitro processing of amyloid precursor protein by cathepsin D

Sadik, Golam; Kaji, Hiroyuki; Takeda, Kazuya; Yamagata, Fumino; Kameoka, Yosuke; Hashimoto, Katsuyuki; Miyanaga, Kazuo; Shinoda, Tomotaka

doi:10.1016/s1357-2725(99)00053-9

Cited by 36 publications

(26 citation statements)

References 36 publications

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“…␥-secretase-independent proteases, which have been suggested by some authors (62)(63)(64). For example, cathepsin D (the major soluble protease of the lysosome) is capable of cleaving soluble APP fragments at positions 42 and 43 (but not 40) (65).…”

Section: Ps-1 App and Nicastrin Are Resident Lysosomalmentioning

confidence: 98%

Presenilin-1, Nicastrin, Amyloid Precursor Protein, and γ-Secretase Activity Are Co-localized in the Lysosomal Membrane

Pasternak

Bagshaw

Guiral

et al. 2003

Journal of Biological Chemistry

276

145

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Alzheimer's disease (AD) is caused by the cerebral deposition of ␤-amyloid (A␤), a 38 -43-amino acid peptide derived by proteolytic cleavage of the amyloid precursor protein (APP). Initial studies indicated that final cleavage of APP by the ␥-secretase (a complex containing presenilin and nicastrin) to produce A␤ occurred in the endosomal/lysosomal system. However, other studies showing a predominant endoplasmic reticulum localization of the ␥-secretase proteins and a neutral pH optimum of in vitro ␥-secretase assays have challenged this conclusion. We have recently identified nicastrin as a major lysosomal membrane protein. In the present work, we use Western blotting and immunogold electron microscopy to demonstrate that significant amounts of mature nicastrin, presenilin-1, and APP are co-localized with lysosomal associated membrane protein-1 (cAMP-1) in the outer membranes of lysosomes. Furthermore, we demonstrate that these membranes contain an acidic ␥-secretase activity, which is immunoprecipitable with an antibody to nicastrin. These experiments establish APP, nicastrin, and presenilin-1 as resident lysosomal membrane proteins and indicate that ␥-secretase is a lysosomal protease. These data reassert the importance of the lysosomal/endosomal system in the generation of A␤ and suggest a role for lysosomes in the pathophysiology of AD.

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Section: Ps-1 App and Nicastrin Are Resident Lysosomalmentioning

confidence: 98%

Presenilin-1, Nicastrin, Amyloid Precursor Protein, and γ-Secretase Activity Are Co-localized in the Lysosomal Membrane

Pasternak

Bagshaw

Guiral

et al. 2003

Journal of Biological Chemistry

276

145

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“…General protein degradation and turnover Many (including ↓) [36] Activation and degradation of polypeptide hormones, FGF [37] chemokines, growth factors and their receptors Plasminogen [38] Prolactin [39,40] Endostatin [41] Osteocalcin [42] Thyroglobulin [43] Insulin [44] Glucagon [45] IL-1 [46] IGFBP [47] Androgen receptor [48] Parathyroid hormone [49] MIP-1 alpha [50] MIP-1 beta [50] SLC [50] Activation of enzymatic precursors Cathepsin B [51,52] Cathepsin L [51,53] Transglutaminase 1 [54] Brain antigen processing Amyloid beta A4 protein [55,56] Tau [57] Tubulin [58] Myelin basic protein [59] Mhtt [60] Apolipoprotein E [61] Alpha-synuclein [62] Degradation of cytoskeletal proteins Neurofilaments [63] Actin [64,65] Myosin [64,66] Tropomyosin [65] Monocyte-mediated fibrinolysis Fibrinogen [67,68] Fibrin [67,68] Regulation of apoptosis Bid [69] Thiredoxin-1 [70] Processing of enzyme activators and inhibitors Prosaposin …”

Section: Biological Function Target Protein Referencementioning

confidence: 99%

Cathepsin D—Many functions of one aspartic protease

Beneš

Větvička

Fusek

2008

Critical Reviews in Oncology/Hematology

532

474

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For years, it has been held that cathepsin D (CD) is involved in rather nonspecific protein degradation in a strongly acidic milieu of lysosomes. Studies with CD knock-out mice revealed that CD is not necessary for embryonal development but it is indispensable for postnatal tissue homeostasis. Mutation that abolishes CD enzymatic activity causes neuronal ceroid lipofuscinosis (NCL) characterized by severe neurodegeneration, developmental regression, visual loss and epilepsy in both animals and humans.In the last decade, however, an increasing number of studies demonstrated that enzymatic function of CD is not restricted solely to acidic milieu of lysosomes with important consequences in regulation of apoptosis. In addition to CD enzymatic activity, it has been shown that apoptosis is also regulated by catalytically inactive mutants of CD which suggests that CD interacts with other important molecules and influences cell signaling.Moreover, procathepsin D, secreted from cancer cells, acts as a mitogen on both cancer and stromal cells and stimulates their pro-invasive and pro-metastatic properties. Numerous studies found that pCD/CD level represents an independent prognostic factor in a variety of cancers and is therefore considered to be a potential target of anti-cancer therapy.Studies dealing with functions of cathepsin D are complicated by the fact that there are several simultaneous forms of CD in a cell -pCD, intermediate enzymatically active CD and mature heavy and light chain CD. It became evident that these forms may differently regulate the above mentioned processes.In this article, we review the possible functions of CD and its various forms in cells and organisms during physiological and pathological conditions.

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“…One protein that may provide this activity is the acidic aspartyl protease Cathepsin D (CTSD). CTSD is capable of producing A␤ in assays where A␤PP fragments equivalent to those produced after cleavage by ␤-secretase are provided [36,37]. In human brain, BACE1 protein appears to provide most of the ␤-secretase activity generating A␤ [38] (although in vitro studies have indicated that CTSD may also cleave A␤PP at its ␤-site raising the possibility that this one protease may be sufficient to produce A␤ from A␤PP [39]).…”

Section: Are Presenilins the Only ␥-Secretases?mentioning

confidence: 99%

Evidence For and Against a Pathogenic Role of Reduced γ-Secretase Activity in Familial Alzheimer’s Disease

Jayne

Newman

Verdile

et al. 2016

JAD

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Abstract. The majority of mutations causing familial Alzheimer's disease (fAD) have been found in the gene PRESENILIN1 (PSEN1) with additional mutations in the related gene PRESENILIN2 (PSEN2). The best characterized function of PRESE-NILIN (PSEN) proteins is in ␥-secretase enzyme activity. One substrate of ␥-secretase is encoded by the gene AMYLOID BETA A4 PRECURSOR PROTEIN (A␤PP/APP) that is a fAD mutation locus. A␤PP is the source of the amyloid-␤ (A␤) peptide enriched in the brains of people with fAD or the more common, late onset, sporadic form of AD, sAD. These observations have resulted in a focus on ␥-secretase activity and A␤ as we attempt to understand the molecular basis of AD pathology. In this paper we briefly review some of the history of research on ␥-secretase in AD. We then discuss the main ideas regarding the role of ␥-secretase and the PSEN genes in this disease. We examine the significance of the "fAD mutation reading frame preservation rule" that applies to PSEN1 and PSEN2 (and A␤PP) and look at alternative roles for A␤PP and A␤ in fAD. We present a case for an alternative interpretation of published data on the role of ␥-secretase activity and fAD-associated mutations in AD pathology. Evidence supports a "PSEN holoprotein multimer hypothesis" where PSEN

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In vitro processing of amyloid precursor protein by cathepsin D

Cited by 36 publications

References 36 publications

Presenilin-1, Nicastrin, Amyloid Precursor Protein, and γ-Secretase Activity Are Co-localized in the Lysosomal Membrane

Presenilin-1, Nicastrin, Amyloid Precursor Protein, and γ-Secretase Activity Are Co-localized in the Lysosomal Membrane

Cathepsin D—Many functions of one aspartic protease

Evidence For and Against a Pathogenic Role of Reduced γ-Secretase Activity in Familial Alzheimer’s Disease

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