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Presenilin clinical mutations can affect gamma-secretase activity by different mechanisms.
J Neurochem. 2006 Feb; 96(3):732-42.JN

Abstract

Mutations in human presenilin (PS) genes cause aggressive forms of familial Alzheimer's disease. Presenilins are polytopic proteins that harbour the catalytic site of the gamma-secretase complex and cleave many type I transmembrane proteins including beta-amyloid precursor protein (APP), Notch and syndecan 3. Contradictory results have been published concerning whether PS mutations cause 'abnormal' gain or (partial) loss of function of gamma-secretase. To avoid the possibility that wild-type PS confounds the interpretation of the results, we used presenilin-deficient cells to analyse the effects of different clinical mutations on APP, Notch, syndecan 3 and N-cadherin substrate processing, and on gamma-secretase complex formation. A loss in APP and Notch substrate processing at epsilon and S3 cleavage sites was observed with all presenilin mutants, whereas APP processing at the gamma site was affected in variable ways. PS1-Delta9 and PS1-L166P mutations caused a reduction in beta-amyloid peptide Abeta40 production whereas PS1-G384A mutant significantly increased Abeta42. Interestingly PS2, a close homologue of PS1, appeared to be a less efficient producer of Abeta than PS1. Finally, subtle differences in gamma-secretase complex assembly were observed. Overall, our results indicate that the different mutations in PS affect gamma-secretase structure or function in multiple ways.

Authors+Show Affiliations

Neuronal Cell Biology and Gene Transfer, Center for Human Genetics, Flanders Interuniversity Institute for Biotechnology (VIB4) and K. U. Leuven, Leuven, Belgium.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16405513

Citation

Bentahir, Mostafa, et al. "Presenilin Clinical Mutations Can Affect Gamma-secretase Activity By Different Mechanisms." Journal of Neurochemistry, vol. 96, no. 3, 2006, pp. 732-42.
Bentahir M, Nyabi O, Verhamme J, et al. Presenilin clinical mutations can affect gamma-secretase activity by different mechanisms. J Neurochem. 2006;96(3):732-42.
Bentahir, M., Nyabi, O., Verhamme, J., Tolia, A., Horré, K., Wiltfang, J., Esselmann, H., & De Strooper, B. (2006). Presenilin clinical mutations can affect gamma-secretase activity by different mechanisms. Journal of Neurochemistry, 96(3), 732-42.
Bentahir M, et al. Presenilin Clinical Mutations Can Affect Gamma-secretase Activity By Different Mechanisms. J Neurochem. 2006;96(3):732-42. PubMed PMID: 16405513.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Presenilin clinical mutations can affect gamma-secretase activity by different mechanisms. AU - Bentahir,Mostafa, AU - Nyabi,Omar, AU - Verhamme,Jan, AU - Tolia,Alexandra, AU - Horré,Katrien, AU - Wiltfang,Jens, AU - Esselmann,Hermann, AU - De Strooper,Bart, Y1 - 2006/01/09/ PY - 2006/1/13/pubmed PY - 2006/3/31/medline PY - 2006/1/13/entrez SP - 732 EP - 42 JF - Journal of neurochemistry JO - J Neurochem VL - 96 IS - 3 N2 - Mutations in human presenilin (PS) genes cause aggressive forms of familial Alzheimer's disease. Presenilins are polytopic proteins that harbour the catalytic site of the gamma-secretase complex and cleave many type I transmembrane proteins including beta-amyloid precursor protein (APP), Notch and syndecan 3. Contradictory results have been published concerning whether PS mutations cause 'abnormal' gain or (partial) loss of function of gamma-secretase. To avoid the possibility that wild-type PS confounds the interpretation of the results, we used presenilin-deficient cells to analyse the effects of different clinical mutations on APP, Notch, syndecan 3 and N-cadherin substrate processing, and on gamma-secretase complex formation. A loss in APP and Notch substrate processing at epsilon and S3 cleavage sites was observed with all presenilin mutants, whereas APP processing at the gamma site was affected in variable ways. PS1-Delta9 and PS1-L166P mutations caused a reduction in beta-amyloid peptide Abeta40 production whereas PS1-G384A mutant significantly increased Abeta42. Interestingly PS2, a close homologue of PS1, appeared to be a less efficient producer of Abeta than PS1. Finally, subtle differences in gamma-secretase complex assembly were observed. Overall, our results indicate that the different mutations in PS affect gamma-secretase structure or function in multiple ways. SN - 0022-3042 UR - https://www.unboundmedicine.com/medline/citation/16405513/Presenilin_clinical_mutations_can_affect_gamma_secretase_activity_by_different_mechanisms_ L2 - https://doi.org/10.1111/j.1471-4159.2005.03578.x DB - PRIME DP - Unbound Medicine ER -