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1.A.54 The Presenilin ER Ca2+ Leak Channel (Presenilin) Family

Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative disorder that affects ~2% of the population in industrialized countries. Mutations in presenilins 1 and 2 (PS1 and PS2) account for ~40% of familial AD cases (Tandon and Fraser, 2002). Familial AD mutations and genetic deletions of presenilins have been associated with calcium (Ca2+) signaling abnormalities. Tu et al. (2006) have demonstrated that wild-type presenilins, but not PS1-M146V and PS2-N141I familial AD mutants, can form low-conductance divalent-cation-permeable ion channels in planar lipid bilayers. In experiments with PS1/2 double knockout mouse embryonic fibroblasts, they found that presenilins account for 80% of passive Ca2+ leak from the endoplasmic reticulum. Deficient Ca2+ signaling in double knockout fibroblasts can be rescued by expression of wild-type PS1 or PS2 but not by expression of PS1-M146V or PS2-N141I mutants. The ER Ca2+ leak function of presenilins is independent of their γ-secretase activity. The data of Tu et al. (2006) suggest a Ca2+ signaling function for presenilins and provide support for the 'Ca2+ hypothesis of AD.' The presenilin 1 calcium leak conductance pore involves TMSs 7 and 9, but not 6, as well as a hydrophilic catalytic cavity (Nelson et al., 2011).  Presenilins play a role in calcium-mediated lysosomal fusion (Bezprozvanny 2012; Coen et al. 2012).

Familial Alzheimer's disease (FAD) mutant presenilin 1 (PS1) (M146L) and PS2 (N141I) interact with the inositol 1,4,5-trisphosphate receptor (InsP3R) Ca2+ release channel and exert profound stimulatory effects on its gating activity in response to saturating and suboptimal levels of InsP3. These interactions result in exaggerated cellular Ca2+ signaling in response to agonist stimulation as well as enhanced low-level Ca2+ signaling in unstimulated cells. Parallel studies in InsP3R-expressing and -deficient cells revealed that enhanced Ca2+ release from the endoplasmic reticulum as a result of the specific interaction of PS1-M146L with the InsP3R stimulates amyloid beta processing, an important feature of AD pathology. These observations provide molecular insights into the 'Ca2+ dysregulation' hypothesis of AD pathogenesis and suggest novel targets for therapeutic intervention (Cheung et al., 2008).

Most cases of AD are idiopathic and are characterized by late onset (>60 years of age). A small fraction of AD cases (familial AD) are characterized by an earlier onset and genetic inheritance. Presenilins are 50 kDa proteins that contain nine transmembrane domains (Laudon et al., 2005) and reside in the endoplasmic reticulum (ER) membrane. They maintain a 9 TMS topology throughout the secretory pathway (Spasic et al., 2006). The complex of presenilins with nicastrin (NCT), APH-1 and PEN-2 subunits functions as γ-secretase, which cleaves the amyloid precursor protein (APP) and releases the amyloid β-peptide (Aβ), the principal constituent of the amyloid plaques in the brains of AD patients. Consistent with the role of presenilins as catalytic subunits of γ-secretase, familial AD mutations in presenilins affect APP processing. These familial AD mutations also result in deranged calcium (Ca2+) signaling (reviewed in Smith et al., 2005). Tu et al. (2006) established that presenilins function as passive ER Ca2+ leak channels and that the familial AD mutations of presenilins affect their ability to conduct Ca2+ ions. These results provide new insight into the normal physiological function of presenilins and strengthen the emerging connection between deranged neuronal Ca2+ signaling and AD.

Presenilin-1 (γ-secretase) is a multisubunit aspartate protease requiring the coordinated action of presenilins (PSs) (Wolfe and Kopan, 2004), nicastrin (NCT), PEN-2 and APH-1 and is crucial for the intramembrane proteolysis of type I membrane proteins such as the amyloid precursor protein (APP) and Notch. The catalytic component, PS1, is a polytopic membrane protein that undergoes endoproteolysis resulting in stable PS1 NH2- and COOH-terminal fragments (PS1-NTF and -CTF). PS1 has 9 TMSs (Spasic et al., 2006).

Presenilin-associated rhomboid-like (PARL) is an inner mitochondrial membrane rhomboid, belonging to a family of evolutionarily conserved integral membrane proteases that participate in signaling. The yeast orthologue is involved in mitochondrial fusion. PARL associates with presenilins 1 and 2 and cleaves type 1 transmembrane proteins. Parl-/- mice undergo progressive atrophy leading to death, due to increased apoptosis. Parl-/- cells are not protected against intrinsic apoptotic death stimuli by the dynamin-related mitochondrial protein OPA1 (Cipolat et al., 2006).

The hydrophilic 'catalytic pore' structure of γ-secretase is formed by TMSs 6, 7 and 9 of presenilin 1 (PS1), the catalytic subunit of γ-secretase in the membrane. The first hydrophobic region, putative TMS1 of PS1, is located in proximity to the catalytic GxGD and PAL motifs within the C-terminal fragment of PS1, facing directly the catalytic pore (Takagi et al., 2010).

Presenilins show a region of similarity (residues 217-305 in PS-2) with the 'Bacteroides development protein' (TC #9.A.18.1.2) BacA (residues 53-149 in this 420 aa protein) of Rhizobium meliloti (e-value of 0.001). Most homologues are from eukaryotes (both plants and animals), but a distant homologue is found in the halobacterial archaeon, Haloquadratum walsbyi (TC #1.A.54.2.1). Many other archaea encode homologues in their genomes, but they do not appear to be present in bacteria.

The transport reaction catalyzed by presenilins is:

Ca2+ (out) Ca2+ (in).

 

References associated with 1.A.54 family:

Annaert, W. and B. De Strooper. (2002). A cell biological perspective on Alzheimer's disease. Annu. Rev. Cell Dev. Biol. 18: 25-51. 12142279
Bezprozvanny, I. (2012). Presenilins: a novel link between intracellular calcium signaling and lysosomal function? J. Cell Biol. 198: 7-10. 22778275
Cheung, K.H., D. Shineman, M. Müller, C. Cárdenas, L. Mei, J. Yang, T. Tomita, T. Iwatsubo, V.M. Lee, and J.K. Foskett. (2008). Mechanism of Ca2+ disruption in Alzheimer's disease by presenilin regulation of InsP3 receptor channel gating. Neuron. 58: 871-883. 18579078
Cipolat, S., T. Rudka, D. Hartmann, V. Costa, L. Serneels, K. Craessaerts, K. Metzger, C. Frezza, W. Annaert, L. D'Adamio, C. Derks, T. Dejaegere, L. Pellegrini, R. D'Hooge, L. Scorrano, and B. De Strooper. (2006). Mitochondrial rhomboid PARL regulates cytochrome c release during apoptosis via OPA1-dependent cristae remodeling. Cell 126: 163-175. 16839884
Coen, K., R.S. Flannagan, S. Baron, L.R. Carraro-Lacroix, D. Wang, W. Vermeire, C. Michiels, S. Munck, V. Baert, S. Sugita, F. Wuytack, P.R. Hiesinger, S. Grinstein, and W. Annaert. (2012). Lysosomal calcium homeostasis defects, not proton pump defects, cause endo-lysosomal dysfunction in PSEN-deficient cells. J. Cell Biol. 198: 23-35. 22753898
Eckert, G.P. and W.E. Müller. (2009). Presenilin 1 modifies lipid raft composition of neuronal membranes. Biochem. Biophys. Res. Commun. 382: 673-677. 19292975
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Laudon, H., E.M. Hansson, K. Melen, A. Bergman, M.R. Farmery, B. Winblad, U. Lendahl, G. von Heijne, and J. Naslund. (2005). A nine-transmembrane domain topology for presenilin 1. J. Biol. Chem. 280: 35352-35360. 16046406
Nelson, O., C. Supnet, A. Tolia, K. Horré, B. De Strooper, and I. Bezprozvanny. (2011). Mutagenesis mapping of the presenilin 1 calcium leak conductance pore. J. Biol. Chem. 286: 22339-22347. 21531718
Smith, I.F., K.N. Green, and F.M. LaFerla. ((2005)). Calcium dysregulation in Alzheimer's disease: recent advances gained from genetically modified animals. Cell Calcium 38: 427-437. 16125228
Spasic, D., A. Tolia, K. Dillen, V. Baert, B. De Strooper, S. Vrijens, and W. Annaert. (2006). Presenilin-1 maintains a nine-transmembrane topology throughout the secretory pathway. J. Biol. Chem. 281: 26569-26577. 16846981
Takagi, S., A. Tominaga, C. Sato, T. Tomita, and T. Iwatsubo. (2010). Participation of transmembrane domain 1 of presenilin 1 in the catalytic pore structure of the γ-secretase. J. Neurosci. 30: 15943-15950. 21106832
Tandon, A. and P. Fraser. (2002). The presenilins. Genome Biol. 3: (E-pub). 12429067
Tu, H., O. Nelson, A. Bezprozvanny, Z. Wang, S.F. Lee, Y.H. Hao, L. Serneels, B. De Strooper, G. Yu, and I. Bezprozvanny. (2006). Presenilins form ER Ca2+ leak channels, a function disrupted by familial Alzheimer's disease-linked mutations. Cell 126: 981-993. 16959576
Wolfe, M.S. and R. Kopan. (2004). Intramembrane proteolysis: theme and variations. Science 305: 1119-1123. 15326347