Presenilin 2

Wolfe MS (2007). When loss is gain reduced presenilin proteolytic function leads to increased AB42/AB40. EMBO Rep 8 136-140... 

Calmyrin is closely related to human calcineurin B. Calmyrin interacts with presenilin 2 and may thus be involved in Alzheimer s disease. 

This type of disease occurs in families and begins unusually at early age (i.e., onset below the age of 60). Approximately 10% of Alzheimer s disease are familial and are inherited in an autosomal dominant manner with high penetrance. Deterministic genes directly cause the disease. Mutations in three different genes encoding for the amyloid precursor protein (APP) and the presenilins 1 and 2 (PS1 and PS2) have been identified to be responsible for early-onset familial Alzheimer s disease. 

Polycystic kidney disease (Polycyst in-1 activates canonical Wnt signaling pathway) Injury-induced renal fibrosis Heart failure Ulcerative colitis Osteoporosis-Pseudoglioma Syndrome (genetic syndrome of defective bone formation) Ulcerative colitis Familial Alzheimer s disease (through interaction with Presenilin-1) Familial Alzheimer s disease (through interaction with Presenilin-1)... 

Hardy, J (1997) Amyloid, the presenilins and Alzheimer s disease. Trends Neurosci. 20 154-159. 

Selkoe, D. J. (1998). The cell biology of beta-amyloid precursor protein and presenilin in Alzheimer s disease. Trends Cell Biol. 8, 447-453. 

Protein-protein interactions between heterodimeric protein pairs that form only transient interactions can be detected, y-secre-tase is presenilin-1 (PS1) dependent [51-53]. PS1 is a 467-amino acid, 9-transmembrane domain protein. Over 100 documented single point mutations are known to cause autosomal-dominant familial AD (FAD) [54], in which the ratio of the more fibrilogenic variety of A ft (A/142) to the less fibrilogenic variety (A/140) is increased. Chinese hamster ovary (CHO) cells were stably transfected with human APP and either wild type or mutant PS1 [4, 55]. 

Berezovska, O., Lleo, A., Fieri, L. D., Frosch, M. P., Stern, E. A., Bacskai, B. J. and Flyman, B. T. (2005). Familial Alzheimer s disease presenilin 1 mutations cause alterations in the conformation of presenilin and interactions with amyloid precursor protein. J. Neurosci. 25, 3009-17. 

Berezovska, O., Jack, C., McLean, P., Aster, J. C., Hicks, C., Xia, W., Wolfe, M. S., Weinmaster, G., Selkoe, D. J. and Hyman, B. T. (2000). Rapid Notch 1 nuclear translocation after ligand binding depends on presenilin-associated gamma-secretase activity. Ann. N.Y. Acad. Sci. 

Kornilova, A.Y., Bihel, F., Das, C., and Wolfe, M.S. (2005) The initial substrate-binding site of y-sccrctasc is located on presenilin near the active site. Proc. Natl Acad. Sci. USA 102, 3230-3235. 

Amyloid precursor protein (APP), presenilin-1, presenilin-2, parkin, tau, huntingtin, ataxin-3... 

PSEN1 Presenilin 1 14q24 Dominant AP production (AP AP10 ratio )... 

De Strooper, B. Aph-1, Pen-2, and nicastrin with presenilin generate an active gamma-secretase complex. Neuron 38 9-12, 2003. 

Selkoe, D. and Kopan, R. Notch and presenilin regulated intramembrane proteolysis links development and degeneration. Annu. Rev. Neurosci. 26 565-597,2003. 

Takasugi, N., Tomita, T., Hayashi, I. et al. The role of presenilin cofactors in the gamma-secretase complex. Nature 422 438M41,2003. 

Thinakaran, G., Harris, C. L., Ratovitski, T. et al. Evidence that levels of presenilins (PS1 and PS2) are coordinately regulated by competition for limiting cellular factors. J. Biol. Chem. 272 28415-28422,1997. 

Edbauer, D., Winkler, E., Haass, C. and Steiner, H. Presenilin and nicastrin regulate each other and determine amyloid beta- peptide production via complex formation. Proc. Natl Acad. Sci. USA 99 8666-8671, 2002. 

Koo, E. H. and Kopan, R. Potential role of presenilin-regulated signaling pathways in sporadic neurodegeneration. Nature Med. 10 Suppl S26-S33, 2004. 

Li, T., Ma, G., Cai, H. etal. Nicastrin is required for assembly of presenilin/gamma-secretase complexes to mediate notch signaling and for processing and trafficking of beta-amyloid precursor protein in mammals. /. Neurosci. 23 3272-3277, 2003. 

Steiner, H., Winkler, E., Edbauer, D. et al. PEN-2 is an integral component of the gamma-secretase complex required for coordinated expression of presenilin and nicastrin. /. Biol. Chem. 277 39062-39065, 2002. 

Esler,W. P.,Kimberly,W.T.,Ostaszewski,B. L. etal.Transition-state analogue inhibitors of gamma-secretase bind directly to presenilin-1. Nature Cell Biol. 2 428-434,2000. 

Wong,P. C.,Zheng,H.,Chen,H. etal. Presenilin 1 is required for Notchl and Dill expression in the paraxial mesoderm. Nature 387 288-292,1997. 

Capell, A., Steiner,H.,Romig,H. etal. Presenilin-1 differentially facilitates endoproteolysis of the beta-amyloid precursor protein and Notch. Nature Cell Biol. 2 205-211, 2000. 

Borchelt, D. R., Thinakaran, G., Eckman, C. B. et al. Familial Alzheimer s disease-linked presenilin 1 variants elevate A(3 1-42/1-40 ratio in vitro and in vivo. Neuron 17 1005-1013, 1996. 

Borchelt, D. R., Ratovitski, T., Van Lare, J. et al. Accelerated amyloid deposition in the brains of transgenic mice coexpressing mutant presenilin 1 and amyloid precursor proteins. Neuron 19 939-945,1997. 

Jankowsky, J. L., Fadale, D. J., Anderson, J. et al. Mutant presenilins specifically elevate the levels of the 42 residue P-amyloid peptide in vivo evidence for augmentation of a 42-specific y-secretase. Hum. Mol. Genet. 13 159-170, 2004. 

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