The Cytosolic Loop of the γ-Secretase Component Presenilin Enhancer 2 Protects Zebrafish Embryos from Apoptosis
- Zetterberg, H., Campbell, W.A., Yang, H.W., and Xia, W.
- The Journal of biological chemistry 281(17): 11933-11939 (Journal)
- Registered Authors
- Xia, Weiming, Zetterberg, Henrik
- MeSH Terms
- Amyloid Precursor Protein Secretases
- Aspartic Acid Endopeptidases/metabolism
- Embryo, Nonmammalian/cytology
- Embryo, Nonmammalian/metabolism*
- Enzyme Activation
- Membrane Proteins/genetics
- Membrane Proteins/metabolism
- Membrane Proteins/physiology*
- Oligonucleotides, Antisense/pharmacology
- Transcription Factor RelA/genetics
- Transcription Factor RelA/physiology
- Zebrafish/growth & development
- Zebrafish Proteins/genetics
- Zebrafish Proteins/physiology*
- 16507571 Full text @ J. Biol. Chem.
Zetterberg, H., Campbell, W.A., Yang, H.W., and Xia, W. (2006) The Cytosolic Loop of the γ-Secretase Component Presenilin Enhancer 2 Protects Zebrafish Embryos from Apoptosis. The Journal of biological chemistry. 281(17):11933-11939.
The gamma-secretase complex, composed of presenilin, Pen-2, nicastrin, and Aph-1, catalyzes the final cleavage of amyloid precursor protein to generate the toxic amyloid b protein, the major component of plaques in the brains of Alzheimer's disease patients. To understand the in vivo function of Pen-2, we used morphant technology available in zebrafish and transiently knocked down the expression of endogenous Pen-2 by injecting the morpholino (MO) against Pen-2. Two truncated Pen-2 proteins lacking either the cytosolic or the C-terminal domain were expressed in MO injected embryos. This deletion analysis demonstrated that the Pen-2 cytosolic loop is essential for protecting developing embryos from caspase-dependent apoptosis caused by the reduction of Pen-2. Twelve amino acids in the C-terminus of Pen-2 were dispensable and could not rescue the Pen-2 knockdown-induced apoptotic phenotype. Surprisingly, double knockdown of Pen-2 and nuclear factor kappaB (NF-kappaB) component p65 abrogated the single Pen-2 MO-induced caspase activation, indicating that a previously reported pro-apoptotic role of NF-kappaB in some cell types could be manifested in a whole animal, and that knockdown of Pen-2 may trigger a pro-apoptotic activation of NF-kappaB.
Genes / Markers
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes