The DOI matches its Crossref record; 7 of the 7 references it cites were found in a registry or an index.
A Loss of Function Mutation of Presenilin-2 Interferes with Amyloid β-Peptide Production and Notch Signaling
Open accessAbstract
Presenilin-1 (PS1) facilitates gamma-secretase cleavage of the beta-amyloid precursor protein and the intramembraneous cleavage of Notch1. Although Alzheimer's disease-associated mutations in the homologous presenilin (PS2) gene elevate amyloid beta-peptide (Abeta42) production like PS1 mutations, here we demonstrate that a gene ablation of PS2 (unlike that of PS1) in mice does not result in a severe phenotype resembling that of Notch-ablated animals. To investigate the amyloidogenic function of PS2 more directly, we mutagenized a conserved aspartate at position 366 to alanine, because the corresponding residue of PS1 is known to be required for its amyloidogenic function. Cells expressing the PS2 D366A mutation exhibit significant deficits in proteolytic processing of beta-amyloid precursor protein indicating a defect in gamma-secretase activity. The reduced gamma-secretase activity results in the almost complete inhibition of Abeta and p3 production in cells stably expressing PS2 D366A, whereas cells overexpressing the wild-type PS2 cDNA produce robust levels of Abeta and p3. Using highly sensitive in vivo assays, we demonstrate that the PS2 D366A mutation not only blocks gamma-secretase activity but also inactivates PS2 activity in Notch signaling by inhibiting the proteolytic release of the cytoplasmic Notch1 domain. These data suggest that PS2 is functionally involved in Abeta production and Notch signaling by facilitating similar proteolytic cleavages.
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Cites
Candidate gene for the chromosome 1 familial Alzheimer’s disease locus
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Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein
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Self-citationEffects of PS1 Deficiency on Membrane Protein Trafficking in Neurons
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Self-citationIntracellular Generation and Accumulation of Amyloid β-Peptide Terminating at Amino Acid 42
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Self-citationSaura, C. A., Choi, S.-Y., Beglopoulos, V., Malkani, S., Zhang, D., Rao, B. S. S., Chattarji, S., Kelleher, R. J., Kandel, E. R., Duff, K., et al. (2004) · Neuron · doi:10.1016/s0896-6273(04)00182-5 · Cited by 757
Self-citationRezai-Zadeh, K., Shytle, D., Sun, N., Mori, T., Hou, H., Jeanniton, D., Ehrhart, J., Townsend, K., Zeng, J., Morgan, D., et al. (2005) · The Journal of Neuroscience · doi:10.1523/jneurosci.1521-05.2005 · Cited by 713
Self-citationGeling, A., Steiner, H., Willem, M., Bally‐Cuif, L., & Haass, C. (2002) · The EMBO Reports · doi:10.1093/embo-reports/kvf124 · Cited by 497
Self-citationA Portrait of Alzheimer Secretases--New Features and Familiar Faces
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Metadata
- Authors
- Steiner, H., Duff, K., Capell, A., Romig, H., Grim, M. G., Lincoln, S., Hardy, J., Yu, X., Picciano, M., Fechteler, K., Citron, M., Kopan, R., Pesold, B., Keck, S., Baader, M., Tomita, T., Iwatsubo, T., Baumeister, R., & Haass, C.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 1999-10
- Volume
- 274
- Issue
- 40
- Pages
- 28669-28673
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2104636742
- Cited by
- 306
- References
- 7
- FWCI
- 17.82
- Type
- journal article
- Language
- en
- Open access
- hybrid
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- Steiner, H., Duff, K., Capell, A., Romig, H., Grim, M. G., Lincoln, S., Hardy, J., Yu, X., Picciano, M., Fechteler, K., Citron, M., Kopan, R., Pesold, B., Keck, S., Baader, M., Tomita, T., Iwatsubo, T., Baumeister, R., & Haass, C. (1999). A Loss of Function Mutation of Presenilin-2 Interferes with Amyloid β-Peptide Production and Notch Signaling. Journal of Biological Chemistry. https://doi.org/10.1074/jbc.274.40.28669
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