PMID- 15456764
OWN - NLM
STAT- MEDLINE
DCOM- 20050111
LR  - 20210209
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 279
IP  - 49
DP  - 2004 Dec 3
TI  - Nicastrin, presenilin, APH-1, and PEN-2 form active gamma-secretase complexes in 
      mitochondria.
PG  - 51654-60
AB  - Mitochondria are central in the regulation of cell death. Apart from providing 
      the cell with ATP, mitochondria also harbor several death factors that are 
      released upon apoptotic stimuli. Alterations in mitochondrial functions, 
      increased oxidative stress, and neurons dying by apoptosis have been detected in 
      Alzheimer's disease patients. These findings suggest that mitochondria may 
      trigger the abnormal onset of neuronal cell death in Alzheimer's disease. We 
      previously reported that presenilin 1 (PS1), which is often mutated in familial 
      forms of Alzheimer's disease, is located in mitochondria and hypothesized that 
      presenilin mutations may sensitize cells to apoptotic stimuli at the 
      mitochondrial level. Presenilin forms an active gamma-secretase complex together 
      with Nicastrin (NCT), APH-1, and PEN-2, which among other substrates cleaves the 
      beta-amyloid precursor protein (beta-APP) generating the amyloid beta-peptide and 
      the beta-APP intracellular domain. Here we have identified dual targeting 
      sequences (for endoplasmic reticulum and mitochondria) in NCT and showed 
      expression of NCT in mitochondria by immunoelectron microscopy. We also showed 
      that NCT together with APH-1, PEN-2, and PS1 form a high molecular weight complex 
      located in mitochondria. gamma-secretase activity in isolated mitochondria was 
      demonstrated using C83 (alpha-secretase-cleaved C-terminal 83-residue beta-APP 
      fragment from BD8 cells lacking presenilin and thus gamma-secretase activity) or 
      recombinant C100-Flag (C-terminal 100-residue beta-APP fragment) as substrates. 
      Both systems generated an APP intracellular domain, and the activity was 
      inhibited by the gamma-secretase inhibitors l-685,458 or Compound E. This novel 
      localization of NCT, PS1, APH-1, and PEN-2 expands the role and importance of 
      gamma-secretase activity to mitochondria.
FAU - Hansson, Camilla A
AU  - Hansson CA
AD  - Karolinska Institutet and Sumitomo Pharmaceuticals Alzheimer Center (KASPAC), 
      Neurotec, Novum, SE-141 57 Huddinge, Sweden.
FAU - Frykman, Susanne
AU  - Frykman S
FAU - Farmery, Mark R
AU  - Farmery MR
FAU - Tjernberg, Lars O
AU  - Tjernberg LO
FAU - Nilsberth, Camilla
AU  - Nilsberth C
FAU - Pursglove, Sharon E
AU  - Pursglove SE
FAU - Ito, Akira
AU  - Ito A
FAU - Winblad, Bengt
AU  - Winblad B
FAU - Cowburn, Richard F
AU  - Cowburn RF
FAU - Thyberg, Johan
AU  - Thyberg J
FAU - Ankarcrona, Maria
AU  - Ankarcrona M
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20040928
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Amyloid beta-Peptides)
RN  - 0 (Amyloid beta-Protein Precursor)
RN  - 0 (Cholic Acids)
RN  - 0 (Detergents)
RN  - 0 (Membrane Glycoproteins)
RN  - 0 (Membrane Proteins)
RN  - 0 (PSEN1 protein, human)
RN  - 0 (PSENEN protein, human)
RN  - 0 (Peptides)
RN  - 0 (Presenilin-1)
RN  - 0 (nicastrin protein)
RN  - 82473-24-3 (chapso)
RN  - 8L70Q75FXE (Adenosine Triphosphate)
RN  - EC 3.4.- (APH1A protein, human)
RN  - EC 3.4.- (Amyloid Precursor Protein Secretases)
RN  - EC 3.4.- (Endopeptidases)
RN  - EC 3.4.- (Peptide Hydrolases)
RN  - EC 3.4.23.- (Aspartic Acid Endopeptidases)
RN  - EC 3.4.23.46 (BACE1 protein, human)
SB  - IM
MH  - Adenosine Triphosphate/chemistry
MH  - Alzheimer Disease/metabolism
MH  - Amino Acid Sequence
MH  - Amyloid Precursor Protein Secretases
MH  - Amyloid beta-Peptides/chemistry
MH  - Amyloid beta-Protein Precursor/chemistry
MH  - Animals
MH  - Apoptosis
MH  - Aspartic Acid Endopeptidases
MH  - Brain/metabolism
MH  - Cholic Acids/pharmacology
MH  - Detergents/pharmacology
MH  - Electrophoresis, Polyacrylamide Gel
MH  - Endopeptidases/metabolism
MH  - Endoplasmic Reticulum/metabolism
MH  - Golgi Apparatus/metabolism
MH  - Immunoblotting
MH  - Immunoprecipitation
MH  - Male
MH  - Membrane Glycoproteins/*biosynthesis
MH  - Membrane Proteins/*biosynthesis
MH  - Microscopy, Immunoelectron
MH  - Mitochondria/metabolism
MH  - Molecular Sequence Data
MH  - Neurons/metabolism
MH  - Oxidative Stress
MH  - Peptide Hydrolases
MH  - Peptides/chemistry
MH  - Presenilin-1
MH  - Protein Structure, Tertiary
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Signal Transduction
MH  - Subcellular Fractions/metabolism
EDAT- 2004/10/01 05:00
MHDA- 2005/01/12 09:00
CRDT- 2004/10/01 05:00
PHST- 2004/10/01 05:00 [pubmed]
PHST- 2005/01/12 09:00 [medline]
PHST- 2004/10/01 05:00 [entrez]
AID - S0021-9258(20)69463-7 [pii]
AID - 10.1074/jbc.M404500200 [doi]
PST - ppublish
SO  - J Biol Chem. 2004 Dec 3;279(49):51654-60. doi: 10.1074/jbc.M404500200. Epub 2004 
      Sep 28.