Coordinated and widespread expression of γ-secretase in vivo: evidence for size and molecular heterogeneity

Hébert, Sébastien S.; Serneels, Lutgarde; Dejaegere, Tim; Horré, Katrien; Dabrowski, Michal; Baert, Veerle; Annaert, Wim; Hartmann, Dieter; Strooper, Bart De

doi:10.1016/j.nbd.2004.08.002

Cited by 141 publications

(104 citation statements)

References 62 publications

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“…42 and 43) they are not clear candidates for this role. More likely, lineage-specific ␥-secretase components will be found above and beyond core components, potentially compatible with size differences in ␥-secretase from different tissues (44). Interactions with these components may be affected by FAD mutations, resulting in pleiotropic alterations in activity (e.g., ''inversion,'' loss in cleavage efficacy for one type of substrate yet a simultaneous gain in cleavage efficacy for another type of substrate).…”

Section: Discussionmentioning

confidence: 99%

Dissociated phenotypes in presenilin transgenic mice define functionally distinct γ-secretases

Mastrangelo

Mathews²,

Chishti³

et al. 2005

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

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␥-secretase depends on presence of presenilins (PS), Nct, Aph-1, and PEN-2 within a core complex. This endoproteolytic activity cleaves within transmembrane domains of amyloid-␤ precursor protein (APP) and Notch, and familial Alzheimer's disease (FAD) mutations in PS1 or PS2 genes shift APP cleavage from production of amyloid-␤ (A␤) 40 peptide to greater production of A␤42. Although studies in PS1͞PS2-deficient embryonic cells define overlapping activities for these proteins, in vivo complementation of PS1-deficient animals described here reveals an unexpected spectrum of activities dictated by PS1 and PS2 alleles. Unlike PS1 transgenes, wild-type PS2 transgenes expressed in the mouse CNS support little A␤40 or A␤42 production, and FAD PS2 alleles support robust production of only A␤42. Although wild-type PS2 transgenes failed to rescue Notch-associated skeletal defects in PS1 hypomorphs, a ''gained'' competence in this regard was apparent for FAD alleles of PS2. The range of discrete and divergent processing activities in mice reconstituted with different PS genes and alleles argues against ␥-secretase being a single enzyme with intrinsically relaxed substrate and cleavage site specificities. Instead, our studies define functionally distinct ␥-secretase variants. We speculate that extrinsic components, in combination with core complexes, may tailor functional variants of this enzyme to their preferred substrates.

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Section: Discussionmentioning

confidence: 99%

Dissociated phenotypes in presenilin transgenic mice define functionally distinct γ-secretases

Mastrangelo

Mathews²,

Chishti³

et al. 2005

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

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“…As two presenilin genes and two Aph1 genes exist, at least four different complexes are possible (3,4). We and others have previously shown that the Aph1A complexes are crucial for Notch signaling during embryogenesis (5,6).…”

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confidence: 88%

Deficiency of Aph1B/C-γ-secretase disturbs Nrg1 cleavage and sensorimotor gating that can be reversed with antipsychotic treatment

Dejaegere

Serneels

Schäfer

et al. 2008

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

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Regulated intramembrane proteolysis by ␥-secretase cleaves proteins in their transmembrane domain and is involved in important signaling pathways. At least four different ␥-secretase complexes have been identified, but little is known about their biological role and specificity. Previous work has demonstrated the involvement of the Aph1A-␥-secretase complex in Notch signaling, but no specific function could be assigned to Aph1B/C-␥-secretase. We demonstrate here that the Aph1B/C-␥-secretase complex is expressed in brain areas relevant to schizophrenia pathogenesis and that Aph1B/C deficiency causes pharmacological and behavioral abnormalities that can be reversed by antipsychotic drugs. At the molecular level we find accumulation of Nrg1 fragments in the brain of Aph1BC ؊/؊ mice. Our observations gain clinical relevance by the demonstration that a Val-to-Leu mutation in the Nrg1 transmembrane domain, associated with increased risk for schizophrenia, affects ␥-secretase cleavage of Nrg1. This finding suggests that dysregulation of intramembrane proteolysis of Nrg1 could increase risk for schizophrenia and related disorders.Alzheimer's ͉ knockout ͉ schizophrenia ͉ presenilin ͉ prepulse inhibition

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“…While colocalization of nicastrin with other γ-secretase components will provide an anatomical basis for the site of γ-secretase activity, variations in their distribution may raise the possibility for a γ-secretase-independent function of nicastrin. Earlier studies have shown that nicastrin protein and/or its mRNA are constitutively expressed in a variety of cell lines and tissues including the brain [7,19,41]. Using mouse lines bearing targeted mutations in their PS1 and/ or APP genes, nicastrin immunoreactivity has been demonstrated to be distributed predominantly in neurons throughout the neuroaxis [45].…”

Section: Introductionmentioning

confidence: 99%

Cellular distribution of γ-secretase subunit nicastrin in the developing and adult rat brains

Kodam

Vetrivel

Wang

et al. 2008

Neurobiology of Aging

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Nicastrin and presenilin 1 are integral components of the high molecular weight γ-secretase complexes that regulate proteolytic processing of various type I membrane proteins including amyloid precursor protein and Notch. At present, there is little information regarding the cellular distribution of nicastrin in the developing or adult rat brain. We report here, using immunoblotting and immunohistochemical methods, that nicastrin in the adult rat brain is widely expressed and colocalized with presenilin 1 in select neuronal populations within all major areas, including the basal forebrain, striatum, cortex, hippocampus, amygdala, thalamus, hypothalamus, cerebellum and brainstem. We also observed dense neuropil labeling in many regions in the brain, suggesting that nicastrin gets transported to dendrites and/or axon terminals in the central nervous system. The levels of nicastrin are found to be relatively high at the early stages of postnatal development and then declined gradually to reach the adult profile. At the cellular level, nicastrin is localized predominantly in neuronal cell bodies at early postanatal stages, but is apparent both in cell bodies and dendrites/ neuropil in all brain regions at the later stages. The regulation of nicastrin expression and localization during development and its distribution in a wide spectrum of neurons in the postnatal and adult rat brains provide an anatomical basis to suggest a multifunctional role for the γ-secretase complex in the developing and adult rat brains.

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Coordinated and widespread expression of γ-secretase in vivo: evidence for size and molecular heterogeneity

Cited by 141 publications

References 62 publications

Dissociated phenotypes in presenilin transgenic mice define functionally distinct γ-secretases

Dissociated phenotypes in presenilin transgenic mice define functionally distinct γ-secretases

Deficiency of Aph1B/C-γ-secretase disturbs Nrg1 cleavage and sensorimotor gating that can be reversed with antipsychotic treatment

Cellular distribution of γ-secretase subunit nicastrin in the developing and adult rat brains

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