Alzheimer's Disease Associated Presenilin 1 Interacts with HC5 and ZETA, Subunits of the Catalytic 20S Proteasome

Gassen, Geert Van; Jonghe, Chris De; Pype, Stefan; Criekinge, Wim Van; Julliams, Ann; Vanderhoeven, Inge; Woodrow, Sarah; Beyaert, Rudi; Huylebroeck, Danny; Broeckhoven, Christine Van

doi:10.1006/nbdi.1999.0265

Cited by 22 publications

(10 citation statements)

References 55 publications

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“…The localization of PS in the ER (endoplasmic reticulum) and Golgi and the effects of familial AD-linked PS mutations on protein processing and localization are compatible with a role for PS in protein sorting or trafficking in cells. Independent observations have described an interaction between PS and several proteins involved in vesicle transport (Rab11, RabGDI and syntaxin 5) [17][18][19], protein sorting (IRE1) [20] or degradation (ubiquilin and HC5/ZETA) [21,22]. In addition to localization in the ER and Golgi, PS-NTF/CTF hetrodimers have been localized at synaptic plasma membranes, synaptic adhesion sites and neurite growth cones.…”

Section: Ps and Protein Localizationmentioning

confidence: 99%

Involvement of presenilins in cell-survival signalling pathways

McCarthy

2005

Biochemical Society Transactions

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Familial AD (Alzheimer's disease) is a rare autosomal dominant form of AD, associated with clinical and pathological features similar to those identified in the more prevalent sporadic AD cases. The majority of familial AD cases are caused by mutations in either of the highly homologous PS (presenilins), an essential component of the gamma-secretase enzyme complex, or amyloid precursor protein, a gamma-secretase substrate and the precursor of amyloid beta peptides. The observation that PS are absolutely required for gamma-secretase activity, and parallel studies demonstrating that PS interact with several signalling molecules, modulate their stability or regulate their proteolysis, have led to the suggestion that involvement of PS in additional signalling pathways mediating key cellular functions may contribute to the pathogenesis and progression of neurodegeneration. In this paper, we review PS-regulated molecules, their role in cell signalling and possible involvement in neurodegeneration in patients suffering from AD.

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Section: Ps and Protein Localizationmentioning

confidence: 99%

Involvement of presenilins in cell-survival signalling pathways

McCarthy

2005

Biochemical Society Transactions

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“…Binding FKBP38 C-terminus Anti-apoptosis protein [179] G-protein G 0 C-terminus Brain G-protein [180] GRB2 Growth factor receptor signalling [181] GSK3b N-terminus Serine-threonine protein kinase; Wnt signalling, [101] GFAPe N-terminus Intermediate filament protein [182] HC5/ZETA Loop domain Subunits catalytic 20S proteasome [183] InsP 3 R Calcium release channel [184] IRAK2 Il-1R and NGFR signalling [133] IRE1 Full length Unfolded protein response; g-secretase substrate [185,186] LRP N-terminus Lipid Metabolism; g-secretase substrate [187] Met1…”

Section: Binding Partnermentioning

confidence: 99%

Presenilin-dependent regulated intramembrane proteolysis and γ-secretase activity

McCarthy

Twomey

Wujek

2009

Cell. Mol. Life Sci.

107

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Inhibiting the production of amyloid-beta by antagonising gamma-secretase activity is currently being pursued as a therapeutic strategy for Alzheimer's disease (AD). However, early pre-clinical studies have demonstrated that disruption of presenilin-dependent gamma-secretase alters many presenilin-dependent processes, leading to early lethality in several AD model organisms. Subsequently, transgenic animal studies have highlighted several gross developmental side effects arising from presenilin deficiency. Partial knockdown or tissue-specific knockout of presenilins has identified the skin, vascular and immune systems as very sensitive to loss of presenilin functions. A more appreciative understanding of presenilin biology is therefore demanded if gamma-secretase is to be pursued as a therapeutic target. Herein we review the current understanding of gamma-secretase complexes; their regulation, abundance of interacting partners and diversity of substrates. We also discuss regulation of the gamma-secretase complexes, with an emphasis on the functional role of presenilins in cell biology.

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“…The observed association was enhanced by MIP-1␤ stimulation. Recently, the subunit of proteasome was shown to associate with presenilin-1 (PSEN1) in the cells (46). Presenilin-1 has been shown to be degraded via the proteasome pathway during the development of Alzheimer's disease.…”

Section: Fig 3 Sdf-1␣ and Gp120-induced Cxcr4 Receptor Internalizatmentioning

confidence: 99%

CXCR4/CCR5 Down-modulation and Chemotaxis Are Regulated by the Proteasome Pathway

Fernandis

Cherla

Chernock

et al. 2002

Journal of Biological Chemistry

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Chemokines and their receptors play a critical role in host immune surveillance and are important mediators of human immunodeficiency virus (HIV) pathogenesis and inflammatory response. The chemokine receptors CCR5 and CXCR4, which act as co-receptors along with CD4 for HIV docking and entry, are down-modulated by their respective ligands, MIP-1␤/SDF-1␣ or by the HIV envelope protein, gp120. We have studied the role of the proteasome pathway in the down-regulation of these receptors. Using the yeast and mammalian two-hybrid systems, we observed that the CCR5 receptor is constitutively associated with the subunit of proteasome. Immunoprecipitation studies in CCR5 L1.2 cells revealed that this association was increased with MIP-1␤ stimulation. The proteasome inhibitors, lactacystin and epoxomicin, attenuated MIP-1␤ induced CCR5 downmodulation as detected by fluorescence-activated cell sorter analysis and confocal microscopy. The proteasome inhibitors also inhibited the SDF-1␣ and gp120 protein-induced down-modulation of the CXCR4 receptor in Jurkat cells. However, the inhibitors had no significant effect on the gp120-induced internalization of the CD4 receptor. These inhibitors also blocked cognate ligand-mediated chemotaxis but had no effect on SDF-1␣-induced p44/42 MAP kinase or MIP-1␤-induced p38 kinase activities, thus indicating differential effects of the inhibitors on signaling mediated by these receptors. These results indicate that the CCR5 and CXCR4 receptor down-modulation mechanism and chemotaxis mediated by these receptors are dependent upon proteasome activity.

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Alzheimer's Disease Associated Presenilin 1 Interacts with HC5 and ZETA, Subunits of the Catalytic 20S Proteasome

Cited by 22 publications

References 55 publications

Involvement of presenilins in cell-survival signalling pathways

Involvement of presenilins in cell-survival signalling pathways

Presenilin-dependent regulated intramembrane proteolysis and γ-secretase activity

CXCR4/CCR5 Down-modulation and Chemotaxis Are Regulated by the Proteasome Pathway

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