The γ-secretase complex: machinery for intramembrane proteolysis

Iwatsubo, Takeshi

doi:10.1016/j.conb.2004.05.010

Cited by 158 publications

(39 citation statements)

References 28 publications

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“…Furthermore, N1 did not modify the endogenous expressions of PS1 or PS2, Aph1, Pen2, and nicastrin (Fig. 4B), the four members of the biologically active ␥-secretase complex (46). Finally, N1 did not affect the endogenous expression of the ␤-secretase BACE1 (Fig.…”

Section: Journal Of Biological Chemistrymentioning

confidence: 98%

α-Secretase-derived Fragment of Cellular Prion, N1, Protects against Monomeric and Oligomeric Amyloid β (Aβ)-associated Cell Death

Guillot-Sestier¹,

Sunyach²,

Ferreira³

et al. 2012

Journal of Biological Chemistry

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Background: Cellular prion undergoes ␣-secretase cleavage, yielding N1. We examined whether N1 protects against A␤ monomers and oligomers. Results: N1 protects against A␤ monomers and oligomers prepared from APP-London-expressing human cells and Alzheimer disease-affected brains. Conclusion: N1 could protect from A␤-associated toxicity at the early asymptomatic phase of Alzheimer disease. Significance: These data emphasize the cross-talk between PrP c and ␤APP catabolites.

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Section: Journal Of Biological Chemistrymentioning

confidence: 98%

α-Secretase-derived Fragment of Cellular Prion, N1, Protects against Monomeric and Oligomeric Amyloid β (Aβ)-associated Cell Death

Guillot-Sestier¹,

Sunyach²,

Ferreira³

et al. 2012

Journal of Biological Chemistry

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“…AD is characterized by two hallmark pathological lesions: intracellular neurofibrillary tangles consisting of twisted filaments of hyperphosphorylated tau and extracellular amyloid plaques containing mainly amyloid-β (Aβ) peptide fibrils. Mutations in the amyloid precursor (APP), presenilin-1 (PSEN1), and presenilin-2 (PSEN2) genes account for roughly half of the rare autosomal dominant, early-onset forms of the disease, which usually occurs before age 60 (Goate et al 1991; an increased production of Aβ42 relative to Aβ40 (Iwatsubo 2004). In contrast to early-onset AD, apolipoprotein E (APOE) is the only commonly accepted late-onset AD susceptibility factor (Corder et al 1993;Saunders et al 1993).…”

Section: Introductionmentioning

confidence: 98%

Effects of Ubiquilin 1 on the Unfolded Protein Response

Hiltunen

Romano

et al. 2008

J Mol Neurosci

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Previous studies have implicated the unfolded protein response (UPR) in the pathogenesis of Alzheimer's disease (AD). We previously reported that DNA variants in the ubiquilin 1 (UBQLN1) gene increase the risk for AD. Since UBQLN1 has been shown to play a role in the UPR, we assessed the effects of overexpression and downregulation of UBQLN1 splice variants during tunicamycin-induced ER stress. In addition to previously described transcript variants, TV1 and TV2, we identified two novel transcript variants of UBQLN1 in brain: TV3 (lacking exons 2-4) and TV4 (lacking exon 4). Overexpression of TV1-3, but not TV4 significantly decreased the mRNA induction of UPR-inducible genes, C/EBP homologous protein (CHOP), BiP/GRP78, and protein disulfide isomerase (PDI) during the UPR. Stable overexpression of TV1-3, but not TV4, also significantly decreased the induction of CHOP protein and increased cell viability during the UPR. In contrast, downregulation of UBQLN1 did not affect CHOP mRNA induction, but instead increased PDI mRNA levels. These findings suggest that overexpression UBQLN1 transcript variants TV1-3, but not TV4, exert a protective effect during the UPR by attenuating CHOP induction and potentially increasing cell viability.

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“…The PS-dependent ␥-secretase activity requires the formation of a high-molecular-weight complex containing nicastrin, Aph1, and Pen2 (for review, see Iwatsubo, 2004). The active complex is assembled in a sequential and interdependent manner through the endoplasmic reticulum and Golgi compartments.…”

Section: Introductionmentioning

confidence: 99%

“…The active complex is assembled in a sequential and interdependent manner through the endoplasmic reticulum and Golgi compartments. Nicastrin was shown to function as the receptor for the ␥-secretase substrates (Shah et al, 2005), and Pen2 facilitates the endoproteolytic cleavage of full-length PS to its N-terminal fragment (NTF) and C-terminal fragment (CTF) (Iwatsubo, 2004). Based on the high-molecular-weight nature of the ␥-secretase complex, Schroeter et al (2003) presented data to support the presence of presenilin homodimers at the core of the ␥-secretase complex, and follow-up studies showed that the transmembrane domains are essential for dimer formation (Cervantes et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Deletion of Presenilin 1 Hydrophilic Loop Sequence Leads to Impaired γ-Secretase Activity and Exacerbated Amyloid Pathology

Deng¹,

Tarassishin²,

Kallhoff³

et al. 2006

J. Neurosci.

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␥-Secretase processing of the amyloid precursor protein (APP) generates A␤ 40 and A␤ 42 , peptides that constitute the principal components of the ␤-amyloid plaque pathology of Alzheimer's disease (AD). The ␥-secretase activity is executed by a high-molecular-weight complex of which presenilin 1 (PS1) is an essential component. PS1 is a multi-pass membrane protein, and the large hydrophilic loop domain between transmembrane domains 6 and 7 has been shown to interact with various proteins. To determine the physiological function of the loop domain, we created a strain of PS1 knock-in mice in which the exon 10, which encodes most of the hydrophilic loop sequence, was deleted from the endogenous PS1 gene. We report here that the homozygous exon 10-deleted mice are viable but exhibit drastically reduced ␥-secretase cleavage at the A␤ 40 , but not the A␤ 42 , site. Surprisingly, this reduction of A␤ 40 is associated with exacerbated plaque pathology when expressed on APP transgenic background. Thus, the PS1 loop plays a regulatory role in ␥-secretase processing, and decreased A␤ 40 , not increased A␤ 42 is likely the cause for the accelerated plaque deposition in these animals. Our finding supports a protective role of A␤ 40 against amyloid pathology and raises the possibility that impaired ␥-secretase activity could be the basis for AD pathogenesis in general.

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The γ-secretase complex: machinery for intramembrane proteolysis

Cited by 158 publications

References 28 publications

α-Secretase-derived Fragment of Cellular Prion, N1, Protects against Monomeric and Oligomeric Amyloid β (Aβ)-associated Cell Death

α-Secretase-derived Fragment of Cellular Prion, N1, Protects against Monomeric and Oligomeric Amyloid β (Aβ)-associated Cell Death

Effects of Ubiquilin 1 on the Unfolded Protein Response

Deletion of Presenilin 1 Hydrophilic Loop Sequence Leads to Impaired γ-Secretase Activity and Exacerbated Amyloid Pathology

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