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Presenilin 2 familial Alzheimer's disease mutations result in partial loss of function and dramatic changes in Abeta 42/40 ratios.
J Neurochem. 2005 Jan; 92(2):294-301.JN

Abstract

Gene knockout studies in mice suggest that presenilin 1 (PS1) is the major gamma-secretase and that it contributes disproportionately to amyloid beta (Abeta) peptide generation from beta-amyloid precursor protein (APP), whereas PS2 plays a more minor role. Based on this and other observations we hypothesized that familial Alzheimer's disease (FAD) mutations in PS2 would have a dramatic effect on function in order to have an observable effect on Abeta levels in the presence of normal PS1 alleles. Only four of the eight reported FAD mutations in PS2 have altered function in vitro suggesting that the other variants represent rare polymorphisms rather than disease-causing mutations. In support of our hypothesis, the four verified PS2 FAD mutations cause substantial changes in the Abeta 42/40 ratio, comparable with PS1 mutations that cause very-early-onset FAD. Most of the PS2 mutations also cause a significant decrease in Abeta 40, APP C-terminal fragment (CTF)gamma and Notch intracellular domain (NICD) production suggesting that they are partial loss of function mutations. PS2 M239V, its PS1 homolog M233V, and other FAD mutations within transmembrane (TM) 5 of PS1 differentially affect CTFgamma and NICD production suggesting that TM5 of PS are important for gamma-secretase cleavage of APP but not Notch.

Authors+Show Affiliations

Department of Psychiatry and Genetics, Washington University School of Medicine, St. Louis, Missouri 63110, USA.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

15663477

Citation

Walker, Emily S., et al. "Presenilin 2 Familial Alzheimer's Disease Mutations Result in Partial Loss of Function and Dramatic Changes in Abeta 42/40 Ratios." Journal of Neurochemistry, vol. 92, no. 2, 2005, pp. 294-301.
Walker ES, Martinez M, Brunkan AL, et al. Presenilin 2 familial Alzheimer's disease mutations result in partial loss of function and dramatic changes in Abeta 42/40 ratios. J Neurochem. 2005;92(2):294-301.
Walker, E. S., Martinez, M., Brunkan, A. L., & Goate, A. (2005). Presenilin 2 familial Alzheimer's disease mutations result in partial loss of function and dramatic changes in Abeta 42/40 ratios. Journal of Neurochemistry, 92(2), 294-301.
Walker ES, et al. Presenilin 2 Familial Alzheimer's Disease Mutations Result in Partial Loss of Function and Dramatic Changes in Abeta 42/40 Ratios. J Neurochem. 2005;92(2):294-301. PubMed PMID: 15663477.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Presenilin 2 familial Alzheimer's disease mutations result in partial loss of function and dramatic changes in Abeta 42/40 ratios. AU - Walker,Emily S, AU - Martinez,Maribel, AU - Brunkan,Anne L, AU - Goate,Alison, PY - 2005/1/25/pubmed PY - 2005/5/27/medline PY - 2005/1/25/entrez SP - 294 EP - 301 JF - Journal of neurochemistry JO - J Neurochem VL - 92 IS - 2 N2 - Gene knockout studies in mice suggest that presenilin 1 (PS1) is the major gamma-secretase and that it contributes disproportionately to amyloid beta (Abeta) peptide generation from beta-amyloid precursor protein (APP), whereas PS2 plays a more minor role. Based on this and other observations we hypothesized that familial Alzheimer's disease (FAD) mutations in PS2 would have a dramatic effect on function in order to have an observable effect on Abeta levels in the presence of normal PS1 alleles. Only four of the eight reported FAD mutations in PS2 have altered function in vitro suggesting that the other variants represent rare polymorphisms rather than disease-causing mutations. In support of our hypothesis, the four verified PS2 FAD mutations cause substantial changes in the Abeta 42/40 ratio, comparable with PS1 mutations that cause very-early-onset FAD. Most of the PS2 mutations also cause a significant decrease in Abeta 40, APP C-terminal fragment (CTF)gamma and Notch intracellular domain (NICD) production suggesting that they are partial loss of function mutations. PS2 M239V, its PS1 homolog M233V, and other FAD mutations within transmembrane (TM) 5 of PS1 differentially affect CTFgamma and NICD production suggesting that TM5 of PS are important for gamma-secretase cleavage of APP but not Notch. SN - 0022-3042 UR - https://www.unboundmedicine.com/medline/citation/15663477/Presenilin_2_familial_Alzheimer's_disease_mutations_result_in_partial_loss_of_function_and_dramatic_changes_in_Abeta_42/40_ratios_ L2 - https://doi.org/10.1111/j.1471-4159.2004.02858.x DB - PRIME DP - Unbound Medicine ER -