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Science 6 December 1996:
Vol. 274. no. 5293, pp. 1710 - 1713
DOI: 10.1126/science.274.5293.1710
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Reports

Participation of Presenilin 2 in Apoptosis: Enhanced Basal Activity Conferred by an Alzheimer Mutation

Benjamin Wolozin, *dagger Katsunori Iwasaki, Pasquale Vito, J. Kelly Ganjei, Emanuela Lacanà, Trey Sunderland, Boyu Zhao, John W. Kusiak, Wilma Wasco, Luciano D'Adamio dagger

Overexpression of the familial Alzheimer's disease gene Presenilin 2 (PS2) in nerve growth factor-differentiated PC12 cells increased apoptosis induced by trophic factor withdrawal or beta -amyloid. Transfection of antisense PS2 conferred protection against apoptosis induced by trophic withdrawal in nerve growth factor-differentiated or amyloid precursor protein-expressing PC12 cells. The apoptotic cell death induced by PS2 protein was sensitive to pertussis toxin, suggesting that heterotrimeric GTP-binding proteins are involved. A PS2 mutation associated with familial Alzheimer's disease was found to generate a molecule with enhanced basal apoptotic activity. This gain of function might accelerate the process of neurodegeneration that occurs in Alzheimer's disease, leading to the earlier age of onset characteristic of familial Alzheimer's disease.

B. Wolozin, K. Iwasaki, T. Sunderland, Unit on Alzheimer Biology, Laboratory of Clinical Science, National Institute of Mental Health, Building 10, Room 3D41, 9000 Rockville Pike, Bethesda, MD 20892, USA.
P. Vito, J. K. Ganjei, E. Lacanà, T-Cell Molecular Biology Unit, Laboratory of Cellular and Molecular Immunology, National Institute of Allergy and Infectious Diseases, Building 4, Room 431, 9000 Rockville Pike, Bethesda, MD 20892, USA.
B. Zhao and J. W. Kusiak, Molecular Neurobiology Unit, National Institute of Aging, Cellular Neurobiology Branch, National Institute of Neurological Disorders and Stroke, Gerontology Research Center, 4940 Eastern Avenue, Baltimore, MD 21224, USA.
W. Wasco, Genetics and Aging Unit, Department of Neurology, Massachusetts General Hospital-East, Harvard Medical School, 149 13th Street, Charlestown, MA 02139, USA.
L. D'Adamio, T-Cell Molecular Biology Unit, Laboratory of Cellular and Molecular Immunology, National Institutes of Health, Building 4, Room 111, 9000 Rockville Pike, Bethesda, MD 20892, USA. E-mail: ldadamio{at}atlas.niaid.nih.gov
*   Present address: Department of Pharmacology, Loyola University Medical Center, 2160 South First Avenue, Maywood, IL 60153, USA. E-mail: bwolozi{at}wpo.it.luc.edu

dagger    To whom correspondence should be addressed.

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Caspase-6 Role in Apoptosis of Human Neurons, Amyloidogenesis, and Alzheimer's Disease.
A. LeBlanc, H. Liu, C. Goodyer, C. Bergeron, and J. Hammond (1999)
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L. Pellegrini, B. J. Passer, M. Tabaton, J. K. Ganjei, and L. D'Adamio (1999)
J. Biol. Chem. 274, 21011-21016
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Suicidal Tendencies: Apoptotic Cell Death by Caspase Family Proteinases.
B. B. Wolf and D. R. Green (1999)
J. Biol. Chem. 274, 20049-20052
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Highly Augmented Cytopathic Effect of a Fiber-mutant E1B-defective Adenovirus for Gene Therapy of Gliomas.
N. Shinoura, Y. Yoshida, R. Tsunoda, M. Ohashi, W. Zhang, A. Asai, T. Kirino, and H. Hamada (1999)
Cancer Res. 59, 3411-3416
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C. C. Weihl, G. D. Ghadge, S. G. Kennedy, N. Hay, R. J. Miller, and R. P. Roos (1999)
J. Neurosci. 19, 5360-5369
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S. M. Janicki and M. J. Monteiro (1999)
Am. J. Pathol. 155, 135-144
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A Myristoylated Calcium-binding Protein that Preferentially Interacts with the Alzheimer's Disease Presenilin 2 Protein.
S. M. Stabler, L. L. Ostrowski, S. M. Janicki, and M. J. Monteiro (1999)
J. Cell Biol. 145, 1277-1292
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Neurotrophic factors [activity-dependent neurotrophic factor (ADNF) and basic fibroblast growth factor (bFGF)] interrupt excitotoxic neurodegenerative cascades promoted by a PS1 mutation.
Q. Guo, L. Sebastian, B. L. Sopher, M. W. Miller, G. W. Glazner, C. B. Ware, G. M. Martin, and M. P. Mattson (1999)
PNAS 96, 4125-4130
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{blacksquare} REVIEW : The Presenilins.
M. P. Mattson and Qing Guo (1999)
Neuroscientist 5, 112-124
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Proteolytic Processing of the Alzheimer's Disease Amyloid Precursor Protein within Its Cytoplasmic Domain by Caspase-like Proteases.
A. Weidemann, K. Paliga, U. Durrwang, F. B. M. Reinhard, O. Schuckert, G. Evin, and C. L. Masters (1999)
J. Biol. Chem. 274, 5823-5829
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J. Walter, A. Schindzielorz, J. Grunberg, and C. Haass (1999)
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C.-S. Hong, L. Caromile, Y. Nomata, H. Mori, D. E. Bredesen, and E. H. Koo (1999)
J. Neurosci. 19, 637-643
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E. Jaikaran, G Marcon, L Levesque, P. George-Hyslop, P. Fraser, and A Clark (1999)
J. Cell Sci. 112, 2137-2144
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Overexpression in Neurons of Human Presenilin-1 or a Presenilin-1 Familial Alzheimer Disease Mutant Does Not Enhance Apoptosis.
S. Bursztajn, R. DeSouza, D. L. McPhie, S. A. Berman, J. Shioi, N. K. Robakis, and R. L. Neve (1998)
J. Neurosci. 18, 9790-9799
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A. Takashima, M. Murayama, O. Murayama, T. Kohno, T. Honda, K. Yasutake, N. Nihonmatsu, M. Mercken, H. Yamaguchi, S. Sugihara, et al. (1998)
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Increased Production of Amyloid Precursor Protein Provides a Substrate for Caspase-3 in Dying Motoneurons.
N. Y. Barnes, L. Li, K. Yoshikawa, L. M. Schwartz, R. W. Oppenheim, and C. E. Milligan (1998)
J. Neurosci. 18, 5869-5880
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Regulation of Brain G-protein Go by Alzheimer's Disease Gene Presenilin-1.
A. Smine, X. Xu, K. Nishiyama, T. Katada, P. Gambetti, S. P. Yadav, X. Wu, Y.-C. Shi, S. Yasuhara, V. Homburger, et al. (1998)
J. Biol. Chem. 273, 16281-16288
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J. N. Keller, Q. Guo, F. W. Holtsberg, A. J. Bruce-Keller, and M. P. Mattson (1998)
J. Neurosci. 18, 4439-4450
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In Vivo Expression of an Alternatively Spliced Human Tumor Message That Encodes a Truncated Form of Cathepsin B. SUBCELLULAR DISTRIBUTION OF THE TRUNCATED ENZYME IN COS CELLS.
S. Mehtani, Q. Gong, J. Panella, S. Subbiah, D. M. Peffley, and A. Frankfater (1998)
J. Biol. Chem. 273, 13236-13244
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Secreted beta -Amyloid Precursor Protein Counteracts the Proapoptotic Action of Mutant Presenilin-1 by Activation of NF-kappa B and Stabilization of Calcium Homeostasis.
Q. Guo, N. Robinson, and M. P. Mattson (1998)
J. Biol. Chem. 273, 12341-12351
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A genetic screen for the isolation and characterization of site-specific proteases.
H. J. Sices and T. M. Kristie (1998)
PNAS 95, 2828-2833
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Calbindin D28k blocks the proapoptotic actions of mutant presenilin 1: Reduced oxidative stress and preserved mitochondrial function.
Q. Guo, S. Christakos, N. Robinson, and M. P. Mattson (1998)
PNAS 95, 3227-3232
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Increased amyloidogenic secretion in cerebellar granule cells undergoing apoptosis.
C. Galli, A. Piccini, M. T. Ciotti, L. Castellani, P. Calissano, D. Zaccheo, and M. Tabaton (1998)
PNAS 95, 1247-1252
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Interaction of Presenilins with the Filamin Family of Actin-Binding Proteins.
W. Zhang, S. W. Han, D. W. McKeel, A. Goate, and J. Y. Wu (1998)
J. Neurosci. 18, 914-922
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To Die or Not to Die: An Overview of Apoptosis and Its Role in Disease.
S. W. Hetts (1998)
JAMA 279, 300-307
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Generation of Anti-apoptotic Presenilin-2 Polypeptides by Alternative Transcription, Proteolysis, and Caspase-3 Cleavage.
P. Vito, T. Ghayur, and L. D'Adamio (1997)
J. Biol. Chem. 272, 28315-28320
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Increased Apoptosis Arising from Increased Expression of the Alzheimer's Disease-associated Presenilin-2 Mutation (N141I).
S. Janicki and M. J. Monteiro (1997)
J. Cell Biol. 139, 485-495
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Human Melanocytes as a Model System for Studies of Alzheimer Disease.
M. Yaar and B. A. Gilchrest (1997)
Arch Dermatol 133, 1287-1291
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Nerve Growth Factor-independent Reduction in Choline Acetyltransferase Activity in PC12 Cells Expressing Mutant Presenilin-1.
W. A. Pedersen, Q. Guo, B. K. Hartman, and M. P. Mattson (1997)
J. Biol. Chem. 272, 22397-22400
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Presenilins Are Processed by Caspase-type Proteases.
H. Loetscher, U. Deuschle, M. Brockhaus, D. Reinhardt, P. Nelboeck, J. Mous, J. Grunberg, C. Haass, and H. Jacobsen (1997)
J. Biol. Chem. 272, 20655-20659
   Abstract »    Full Text »    PDF »
Alternative Cleavage of Alzheimer-Associated Presenilins During Apoptosis by a Caspase-3 Family Protease.
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Alzheimer's Presenilin Mutation Sensitizes Neural Cells to Apoptosis Induced by Trophic Factor Withdrawal and Amyloid beta -Peptide: Involvement of Calcium and Oxyradicals.
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A Loss of Function Mutant of the Presenilin Homologue SEL-12 Undergoes Aberrant Endoproteolysis in Caenorhabditis elegans and Increases Abeta 42 Generation in Human Cells.
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