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Science 18 July 1997:
Vol. 277. no. 5324, pp. 373 - 376
DOI: 10.1126/science.277.5324.373
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Reports

Alternative Cleavage of Alzheimer-Associated Presenilins During Apoptosis by a Caspase-3 Family Protease

Tae-Wan Kim, Warren H. Pettingell, Yong-Keun Jung, Dora M. Kovacs, Rudolph E. Tanzi *

Most cases of early-onset familial Alzheimer's disease (FAD) are caused by mutations in the genes encoding the presenilin 1 (PS1) and PS2 proteins, both of which undergo regulated endoproteolytic processing. During apoptosis, PS1 and PS2 were shown to be cleaved at sites distal to their normal cleavage sites by a caspase-3 family protease. In cells expressing PS2 containing the asparagine-141 FAD mutant, the ratio of alternative to normal PS2 cleavage fragments was increased relative to wild-type PS2-expressing cells, suggesting a potential role for apoptosis-associated cleavage of presenilins in the pathogenesis of Alzheimer's disease.

T.-W. Kim, W. H. Pettingell, D. M. Kovacs, R. E. Tanzi, Genetics and Aging Unit, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
Y.-K. Jung, Department of Life Science, KwangJu Institute of Science and Technology, 572 Sangam-dong, Kwangsan-ku, KwangJu, Korea.
*   To whom correspondence should be addressed. E-mail: tanzi{at}helix.mgh.harvard.edu

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D. Vercammen, G. Brouckaert, G. Denecker, M. Van de Craen, W. Declercq, W. Fiers, and P. Vandenabeele (1998)
J. Exp. Med. 188, 919-930
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Molecular Dissection of Domains in Mutant Presenilin 2 That Mediate Overproduction of Amyloidogenic Forms of Amyloid beta  Peptides. INABILITY OF TRUNCATED FORMS OF PS2 WITH FAMILIAL ALZHEIMER'S DISEASE MUTATION TO INCREASE SECRETION OF Abeta 42.
T. Tomita, S. Tokuhiro, T. Hashimoto, K. Aiba, T. C. Saido, K. Maruyama, and T. Iwatsubo (1998)
J. Biol. Chem. 273, 21153-21160
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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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Increased Sensitivity to Mitochondrial Toxin-Induced Apoptosis in Neural Cells Expressing Mutant Presenilin-1 Is Linked to Perturbed Calcium Homeostasis and Enhanced Oxyradical Production.
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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Additional evidence for an eight-transmembrane-domain topology for Caenorhabditis elegans and human presenilins.
X. Li and I. Greenwald (1998)
PNAS 95, 7109-7114
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Proteases to die for.
V. Cryns and J. Yuan (1998)
Genes & Dev. 12, 1551-1570
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Amyloid beta  Protein-(1-42) Forms Calcium-permeable, Zn2+-sensitive Channel.
S. K. Rhee, A. P. Quist, and R. Lal (1998)
J. Biol. Chem. 273, 13379-13382
   Abstract »    Full Text »    PDF »
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
   Abstract »    Full Text »    PDF »
Inhibition of Caspases Increases the Sensitivity of L929 Cells to Necrosis Mediated by Tumor Necrosis Factor.
D. Vercammen, R. Beyaert, G. Denecker, V. Goossens, G. Van Loo, W. Declercq, J. Grooten, W. Fiers, and P. Vandenabeele (1998)
J. Exp. Med. 187, 1477-1485
   Abstract »    Full Text »    PDF »
Caspase Cleavage of Gene Products Associated with Triplet Expansion Disorders Generates Truncated Fragments Containing the Polyglutamine Tract.
C. L. Wellington, L. M. Ellerby, A. S. Hackam, R. L. Margolis, M. A. Trifiro, R. Singaraja, K. McCutcheon, G. S. Salvesen, S. S. Propp, M. Bromm, et al. (1998)
J. Biol. Chem. 273, 9158-9167
   Abstract »    Full Text »    PDF »
MEK Kinase 1, a Substrate for DEVD-Directed Caspases, Is Involved in Genotoxin-Induced Apoptosis.
C. Widmann, P. Gerwins, N. L. Johnson, M. B. Jarpe, and G. L. Johnson (1998)
Mol. Cell. Biol. 18, 2416-2429
   Abstract »    Full Text »
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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The Genetics of Alzheimer Disease: Current Status and Future Prospects.
D. Blacker and R. E. Tanzi (1998)
Arch Neurol 55, 294-296
   Abstract »    Full Text »    PDF »
The Proteolytic Fragments of the Alzheimer's Disease-associated Presenilin-1 Form Heterodimers and Occur as a 100-150-kDa Molecular Mass Complex.
A. Capell, J. Grunberg, B. Pesold, A. Diehlmann, M. Citron, R. Nixon, K. Beyreuther, D. J. Selkoe, and C. Haass (1998)
J. Biol. Chem. 273, 3205-3211
   Abstract »    Full Text »    PDF »
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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Genetics of Aging.
C. E. Finch and R. E. Tanzi (1997)
Science 278, 407-411
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Molecular Neurogenetics: The Genome Is Settling the Issue.
R. N. Rosenberg (1997)
JAMA 278, 1282-1283
   Abstract »    PDF »
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.
M. Okochi, S. Eimer, A. Bottcher, R. Baumeister, H. Romig, J. Walter, A. Capell, H. Steiner, and C. Haass (2000)
J. Biol. Chem. 275, 40925-40932
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Nuclear Translocation of the N-terminal Prodomain of Interleukin-16.
Y. Zhang, H. Kornfeld, W. W. Cruikshank, S. Kim, C. C. Reardon, and D. M. Center (2001)
J. Biol. Chem. 276, 1299-1303
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Calsenilin Is a Substrate for Caspase-3 That Preferentially Interacts with the Familial Alzheimer's Disease-associated C-terminal Fragment of Presenilin 2.
E.-K. Choi, N. F. Zaidi, J. S. Miller, A. C. Crowley, D. E. Merriam, C. Lilliehook, J. D. Buxbaum, and W. Wasco (2001)
J. Biol. Chem. 276, 19197-19204
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The Nonconserved Hydrophilic Loop Domain of Presenilin (PS) Is Not Required for PS Endoproteolysis or Enhanced Abeta 42 Production Mediated by Familial Early Onset Alzheimer's Disease-linked PS Variants.
C. A. Saura, T. Tomita, S. Soriano, M. Takahashi, J.-Y. Leem, T. Honda, E. H. Koo, T. Iwatsubo, and G. Thinakaran (2000)
J. Biol. Chem. 275, 17136-17142
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Presenilin 2 Interacts with Sorcin, a Modulator of the Ryanodine Receptor.
E. Pack-Chung, M. B. Meyers, W. P. Pettingell, R. D. Moir, A. M. Brownawell, I. Cheng, R. E. Tanzi, and T.-W. Kim (2000)
J. Biol. Chem. 275, 14440-14445
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