Caspase-mediated cleavage is not required for the activity of presenilins in amyloidogenesis and NOTCH signaling

Brockhaus, Manfred; Grünberg, Jürgen; Röhrig, Sascha; Loetscher, Hansruedi; Wittenburg, Nicole; Baumeister, Ralf; Jacobsen, Helmut; Haass, Christian

doi:10.1097/00001756-199805110-00043

Cited by 73 publications

(59 citation statements)

References 7 publications

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“…Furthermore, our analyses of A␤ secreted from cells expressing PS1⌬HL or PS2⌬HL harboring FAD-linked mutations strongly argues against a role for caspase cleavage within the HL domain in mediating the effects of FAD mutations on A␤42 generation. A similar conclusion regarding the connection between caspase cleavage and A␤42 production was reached in an earlier study (49). Although our studies provide clear evidence that under normal culture conditions caspase cleavage of PS does not contribute to enhanced production of A␤42 by mutant PS, we cannot rule out a role for caspase cleavage of PS in influencing A␤42 production under pathogenic conditions in vivo.…”

Section: Fig 7 Lack Of Requirement Of the Ps Hl Domain For Notch Prsupporting

confidence: 86%

The Nonconserved Hydrophilic Loop Domain of Presenilin (PS) Is Not Required for PS Endoproteolysis or Enhanced Aβ42 Production Mediated by Familial Early Onset Alzheimer's Disease-linked PS Variants

Saura¹,

Tomita²,

Soriano³

et al. 2000

Journal of Biological Chemistry

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Presenilin 1 (PS1) and presenilin 2 (PS2) are polytopic membrane proteins that are mutated in the majority of early onset familial Alzheimer's disease (FAD) cases. Two lines of evidence establish a critical role for PS in the production of ␤-amyloid peptides (A␤). FAD-linked PS mutations elevate the levels of highly amyloidogenic A␤ ending at residue 42 (A␤42), and cells with ablated PS1 alleles secrete low levels of A␤. Several recent reports have shown that the hydrophilic loop (HL) domain, located between transmembrane domains 6 and 7, contains sites for phosphorylation, caspase cleavage, and sequences that bind several PS-interacting proteins. In the present report, we examined the metabolism of PS polypeptides lacking the HL domain and the influence of these molecules on A␤ production. We report that the deletion of the HL domain does not have a deleterious effect on the regulated endoproteolysis of PS, saturable accumulation of PS fragments, or the selfassociation of PS fragments. A␤ production was not significantly altered in cells expressing HL-deleted PS polypeptides compared with cells expressing full-length PS. Importantly, deletion of the HL domain did not affect FAD mutation-mediated elevation in the production of A␤42. Furthermore, the deletion of the HL domain did not impair the role of PS1 or PS2 in facilitating Notch processing. Thus, our results argue against a biologically or pathologically relevant role for the HL domain phosphorylation and caspase cleavage and the association of PS HL domain-interacting proteins, in amyloid precursor protein metabolism and A␤ production or Notch cleavage.Autosomal dominant mutations in genes encoding presenilin 1 (PS1) 1 and presenilin 2 (PS2) predispose individuals to familial early onset Alzheimer's disease (FAD) (1-3). Alzheimer's disease is pathologically characterized by the cerebral deposition of 40 -42 amino acid ␤-amyloid (A␤) peptides, which are generated by the proteolytic processing of amyloid precursor protein (APP) (4, 5). PSs play an important role in the generation of A␤, as evidenced by the lack A␤ production in cells established from PS1 Ϫ/Ϫ mice (6, 7). Furthermore, FAD-linked mutations in PS increase the production of highly fibrillogenic A␤42 (8 -11). PS are polytopic membrane proteins that undergo regulated endoproteolysis to generate saturable of stable NH 2 -(NTF) and COOH-terminal fragments (CTF), which are the preponderant PS-related species that accumulate in vivo (12,13). Although the precise steps involved in the maturation of synthetic PS polypeptides are not clearly defined, properly folded PS polypeptides are stabilized, undergo endoproteolysis, and form high molecular weight complexes (13-18). The vast majority of overexpressed full-length PS and transgene-derived polypeptides that correspond to the NTF fail to form stable complexes and are rapidly degraded (15,18,19). Whereas endoproteolytic cleavage is not required for biological activity of PS polypeptides (12,20,21), several lines of evidence indicate that the NTF and CTF ...

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Section: Fig 7 Lack Of Requirement Of the Ps Hl Domain For Notch Prsupporting

confidence: 86%

The Nonconserved Hydrophilic Loop Domain of Presenilin (PS) Is Not Required for PS Endoproteolysis or Enhanced Aβ42 Production Mediated by Familial Early Onset Alzheimer's Disease-linked PS Variants

Saura¹,

Tomita²,

Soriano³

et al. 2000

Journal of Biological Chemistry

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“…1C). However, we and others (31)(32)(33)(34) have shown previously that the endogenous PS1 CTF 20 can be an in vivo substrate for an additional cleavage mediated by a proteinase of the caspase superfamily even without the induction of apoptosis (Fig. 1A).…”

Section: Fig 2 Ntf 298 Is Rapidly Degraded By the Proteasome And Ismentioning

confidence: 66%

“…4C), therefore indicating that calpain-like proteinases are most likely involved in its degradation. Previously, we and others (32)(33)(34) have noticed that the amounts of CTF 10 are highly variable depending on the cell line or tissue analyzed. We therefore analyzed CTF 10 degradation in another cell type.…”

Section: Fig 2 Ntf 298 Is Rapidly Degraded By the Proteasome And Ismentioning

confidence: 94%

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Expression of Alzheimer’s Disease-associated Presenilin-1 Is Controlled by Proteolytic Degradation and Complex Formation

Steiner¹,

Capell²,

Pesold³

et al. 1998

Journal of Biological Chemistry

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185

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Numerous mutations causing early onset Alzheimer's disease have been identified in the presenilin (PS) genes, particularly the PS1 gene. Like the mutations identified within the ␤-amyloid precursor protein gene, PS mutations cause the increased generation of a highly neurotoxic variant of amyloid ␤-peptide. PS proteins are proteolytically processed to an N-terminal ϳ30-kDa (NTF) and a C-terminal ϳ20-kDa fragment (CTF 20 ) that form a heterodimeric complex. We demonstrate that this complex is resistant to proteolytic degradation, whereas the full-length precursor is rapidly degraded. Degradation of the PS1 holoprotein is sensitive to inhibitors of the proteasome. Formation of a heterodimeric complex is required for the stability of both PS1 fragments, since fragments that do not co-immunoprecipitate with the PS complex are rapidly degraded by the proteasome. Mutant PS fragments not incorporated into the heterodimeric complex lose their pathological activity in abnormal amyloid ␤-peptide generation even after inhibition of their proteolytic degradation. The PS1 heterodimeric complex can be attacked by proteinases of the caspase superfamily that generate an ϳ10-kDa proteolytic fragment (CTF 10 ) from CTF 20 . CTF 10 is rapidly degraded most likely by a calpain-like cysteine proteinase. From these data we conclude that PS1 metabolism is highly controlled by multiple proteolytic activities indicating that subtle changes in fragment generation/ degradation might be important for Alzheimer's diseaseassociated pathology.Alzheimer's disease (AD) 1 is the most common dementia worldwide. A pathological hallmark of AD is the invariant accumulation of numerous senile plaques in certain areas of the brain. Senile plaques are composed of the amyloid ␤-peptide (A␤), a proteolytic derivative of the ␤-amyloid precursor protein (␤APP; see Ref. 1). In the majority of cases, AD occurs as a sporadic disease with an increasing risk during aging (2). However, in about 10 -15% of the cases AD is caused by autosomal dominant mutations within three genes (2). A very limited set of families was identified carrying mutations in the ␤APP gene (2). These mutations occur at, or close to, the cleavage sites of the ␤APP-processing enzymes, the secretases (1). All ␤APP mutations analyzed so far cause an enhanced production of A␤, specifically the highly pathogenic 42-amino acid variant, A␤42 (2).By far the highest number of FAD-associated mutations were identified within the PS gene (see Ref. 3 and for review see Ref. 4). Two mutations were also observed in the highly homologous PS2 gene (5, 6). PS proteins are integral membrane proteins, which form 6 to 8 trans-membrane domains with the N-terminal domain, the large loop, and the C-terminal domain located within the cytoplasm (7,8). Both PS proteins are predominantly expressed within the endoplasmic reticulum, the nuclear envelope, and the early Golgi (7, 9 -12).Like ␤APP mutations, mutant PS proteins are involved in aberrant A␤ generation. All PS1 and PS2 mutations analyzed so far affect the ...

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“…Lipids may also directly promote presenilin maturation. In this regard, it has been proposed that transfer to the high-molecularweight form, and not cleavage itself, is the regulated aspect of presenilin activation (45). The steps in the processing of the sterol regulatory element binding proteins (SREBPs) constitute the best-characterized pathway of lipid-regulated proteolysis (46).…”

Section: Discussionmentioning

confidence: 99%

Fatty acids increase presenilin-1 levels and γ-secretase activity in PSwt-1 cells

Liu

Yang

Conde-Knape

et al. 2004

Journal of Lipid Research

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Caspase-mediated cleavage is not required for the activity of presenilins in amyloidogenesis and NOTCH signaling

Cited by 73 publications

References 7 publications

The Nonconserved Hydrophilic Loop Domain of Presenilin (PS) Is Not Required for PS Endoproteolysis or Enhanced Aβ42 Production Mediated by Familial Early Onset Alzheimer's Disease-linked PS Variants

The Nonconserved Hydrophilic Loop Domain of Presenilin (PS) Is Not Required for PS Endoproteolysis or Enhanced Aβ42 Production Mediated by Familial Early Onset Alzheimer's Disease-linked PS Variants

Expression of Alzheimer’s Disease-associated Presenilin-1 Is Controlled by Proteolytic Degradation and Complex Formation

Fatty acids increase presenilin-1 levels and γ-secretase activity in PSwt-1 cells

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