Presenilin 2 Interacts with Sorcin, a Modulator of the Ryanodine Receptor

Pack-Chung, Eunju; Meyers, Marian B.; Pettingell, Warren H.; Moir, Robert D.; Brownawell, Amy M.; Cheng, Ikp; Tanzi, Rudolph E.; Kim, Tae‐Wan

doi:10.1074/jbc.m909882199

Cited by 102 publications

(68 citation statements)

References 59 publications

(39 reference statements)

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“…Some studies have demonstrated that FAD-related mutant PS may sensitize neurons to apoptosis by perturbing intracellular calcium homeostasis (13,(31)(32)(33). We found that dantrolene treatment suppressed sel-12(ar131)-induced apoptosis, which means that by abnormal regulation of calcium release from the ER, sel-12(ar131) predisposes embryo cells to apoptosis.…”

Section: Discussionmentioning

confidence: 59%

The Role of the Presenilin-1 Homologue Gene sel-12 ofCaenorhabditis elegans in Apoptotic Activities

Kitagawa

Shimohama

Oeda

et al. 2003

Journal of Biological Chemistry

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Many cases of autosomal dominant early onset familial Alzheimer's disease result from mutations in presenilin-1 (PS1). In this study, we examined the role of the PS1 homologue gene sel-12 of Caenorhabditis elegans under oxidative stress and clarified the sel-12-induced apoptosis. A genetic null allele mutant, sel-12(ar171), showed resistance to oxidative stress and prevented mitochondrial dysfunction-induced apoptosis. On the other hand, another allele mutant, sel-12(ar131), that carries a missense mutation showed a proapoptotic activity, which may be the result of a gain of function property. Also, sel-12(ar131)-induced apoptosis was ced-3-and ced-4-dependent. Dantrolene, which specifically inhibits Ca 2؉ release from endoplasmic reticulum stores, prevents sel-12(ar131)-induced apoptosis. SEL-12, which is localized in the endoplasmic reticulum, may induce apoptosis through abnormal calcium release from the endoplasmic reticulum. Together, with the previous finding that human PS1 could substitute for SEL-12, these results suggest the similar involvement of PS1-inducing apoptosis under oxidative stress and mitochondrial dysfunction in the Alzheimer's Disease brain.Many cases of autosomal dominant early onset familial Alzheimer's disease (FAD) 1 result from mutations in the gene encoding presenilin-1 (PS1) (1). PS1 is an integral membrane protein comprising multiple transmembrane domains that is expressed in neurons throughout the brain and primarily localized in the endoplasmic reticulum (ER) and the Golgi apparatus (2, 3). PS1 is essential for ␥-secretase cleavage of the amyloid precursor protein (APP) and Notch protein (4 -7). FAD-related mutations in PS1 increase the levels of A␤42 in Alzheimer's disease brains (8), transfected cell lines, and transgenic animals (9, 10). It is recognized that oxidative stress and mitochondrial abnormalities may play important roles in the pathogenesis of Alzheimer's disease (11,12). Overexpression of PS1 mutations in cultured cells increases their vulnerability to oxidative stress and A␤ toxicity (13, 14). As it is well known that oxidative stress plays the role of apoptosis (15), the oxidative stress and apoptosis may be also tightly linked in Alzheimer's disease. In fact, FAD-related mutant PS1 is also involved in apoptosis (13,16).Caenorhabditis elegans has the PS1 homologue gene sel-12, which facilitates lin-12/Notch receptor-mediated signaling, and the mutation of sel-12 produces defects in vulva and neuronal development (17,18). Levitan et al. (19) have shown that human PS1 could substitute for C. elegans sel-12 protein. In this study, we try to elucidate the possibility that sel-12 is involved in oxidative stress and apoptosis in C. elegans. In attempting to clarify the relationship between sel-12 and cell death, we used the C. elegans sel-12 and mev-1 mutants in this study. The mev-1(kn1) mutant has a defect in the cytochrome b large subunit in complex II of the mitochondrial electron transport chain that shows hypersensitivity to oxygen and paraquat (20). have rep...

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Section: Discussionmentioning

confidence: 59%

The Role of the Presenilin-1 Homologue Gene sel-12 ofCaenorhabditis elegans in Apoptotic Activities

Kitagawa

Shimohama

Oeda

et al. 2003

Journal of Biological Chemistry

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“…Instead, the abnormalities in hippocampal synaptic plasticity are likely the result of the perturbed endoplasmic reticulum Ca 2+ regulation previously documented in studies of cultured neurons expressing FAD PS1 mutations. Those studies showed that PS1 mutations cause Ca 2+ to accumulate at higher levels in the endoplasmic reticulum resulting in an enhanced release of Ca 2+ in response to muscarinic agonists (Guo et al, 1997;Begley et al, 1999;Leissring et al, 2001), as well as enhanced Ca 2+ -induced Ca 2+ release through ryanodine receptors (Chan et al, 2000;Pack-Chung et al, 2000). Apparently, wild-type PS1 functions as a Ca 2+ leak channel in the endoplasmic reticulum membrane, and FAD-linked PS1 mutations impair this Ca 2+ leak function (Tu et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

Presenilin-1 mutation impairs cholinergic modulation of synaptic plasticity and suppresses NMDA currents in hippocampus slices

Wang

Greig

et al. 2009

Neurobiology of Aging

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Presenilin-1 (PS1) mutations cause many cases of early-onset inherited Alzheimer's disease, in part, by increasing the production of neurotoxic forms of amyloid β-peptide (A β). However, Aβ -independent effects of mutant PS1 on neuronal Ca 2+ homeostasis and sensitivity to excitatory neurotransmitters have been reported. Here we show that cholinergic modulation of hippocampal synaptic plasticity is impaired in PS1 mutant knockin (PS1KI) mice. Whereas activation of muscarinic receptors enhances LTP at CA1 synapses of normal mice, it impairs LTP in PS1KI mice. Similarly, mutant PS1 impairs the ability of the cholinesterase inhibitor phenserine to enhance LTP. The NMDA current is decreased in CA1 neurons of PS1KI mice and is restored by intracellular Ca 2+ chelation. Similar alterations in acetylcholine and NMDA receptor-mediated components of synaptic plasticity are evident in 3×TgAD mice with PS1, amyloid precursor protein and tau mutations, suggesting that the adverse effects of mutant PS1 on synaptic plasticity can occur in the absence or presence of amyloid and tau pathologies.

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“…Some PS-associated proteins (e.g. calpain, calmyrin, and sorcin) also bind calcium, and PS has been implicated in intracellular calcium homeostasis (27,(47)(48)(49)(50)(51). In this regard, CALP might have a function in PS-mediated calcium modulation.…”

Section: Effect Of the Overexpression Of Calp On Metabolism Of Ps Polmentioning

confidence: 99%

Molecular Cloning and Characterization of CALP/KChIP4, a Novel EF-hand Protein Interacting with Presenilin 2 and Voltage-gated Potassium Channel Subunit Kv4

Morohashi¹,

Hatano²,

Ohya³

et al. 2002

Journal of Biological Chemistry

148

122

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Presenilin (PS) genes linked to early-onset familialAlzheimer's disease encode polytopic membrane proteins that are presumed to constitute the catalytic subunit of ␥-secretase, forming a high molecular weight complex with other proteins. During our attempts to identify binding partners of PS2, we cloned CALP (calsenilin-like protein)/KChIP4, a novel member of calsenilin/ KChIP protein family that interacts with the C-terminal region of PS. Upon co-expression in cultured cells, CALP was directly bound to and co-localized with PS2 in endoplasmic reticulum. Alzheimer's disease (AD)1 is a progressive dementing neurodegenerative disorder characterized by a massive deposition of ␤-amyloid and tau-rich neurofibrillary lesions in the brains (reviewed in Ref. 1 and references therein). A subset of AD is inherited as an autosomal dominant trait, and mutations in three different genes have thus far been linked to early-onset autosomal dominant forms of familial AD (FAD). Among these, presenilin 1 (PS1) and PS2 account for the majority of the early onset FAD (1). PS1 and PS2 genes encode polytopic integral membrane proteins that are predominantly localized in intracellular membranes and span the membrane six to eight times.PS proteins undergo endoproteolysis to give rise to N-and C-terminal fragments, which are the preponderant forms of endogenous PS in vivo (2). These fragments form a heterodimer and are incorporated into high molecular weight (HMW) protein complexes (2-5) that are highly stabilized (t1 ⁄2 ϭ ϳ20 h; Ref.6), whereas holoproteins of PS are rapidly degraded (t1 ⁄2 ϭ ϳ2 h) (6, 7). The steady-state levels of PS fragments seem to be tightly regulated by competition for shared, but limiting, cellular factors, because overexpression of PS in transfected cells does not increase the overall level of PS fragments and replaces endogenous PS (8).PS plays an important role in the generation of amyloid ␤ peptides (A␤) by facilitating intramembranous ␥-cleavage of ␤-amyloid protein precursor (␤APP), as evidenced by the lack of A␤ production and accumulation of ␤APP C-terminal stubs in cells established from PS-null mice (9 -11). In contrast, FADlinked mutations in PS increase the production of highly fibrillogenic A␤42 (12-15), which is the initial and predominantly deposited A␤ species in AD brains (16, 17) and normally consists of only ϳ10% of total secreted A␤ (18). Moreover, genetic studies in invertebrates and PS-null mice suggested that ␥-cleavage-like proteolytic cleavage at site 3 to release Notch intracellular domain (NICD), which is the prerequisite for Notch signaling (reviewed in Ref. 19), also is facilitated by PS. Furthermore, recent findings that the two intramembranous aspartates within the 6th and 7th transmembrane (TM) domains of PS are required for ␥-secretase activities (20) and that transition state analogue ␥-secretase inhibitors specifically label PS fragments (21-24) strongly support the notion that the PS-containing macroprotein complex catalyzes ␥-cleavage and that PS may represent the catalytic ...

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Presenilin 2 Interacts with Sorcin, a Modulator of the Ryanodine Receptor

Cited by 102 publications

References 59 publications

The Role of the Presenilin-1 Homologue Gene sel-12 ofCaenorhabditis elegans in Apoptotic Activities

The Role of the Presenilin-1 Homologue Gene sel-12 ofCaenorhabditis elegans in Apoptotic Activities

Presenilin-1 mutation impairs cholinergic modulation of synaptic plasticity and suppresses NMDA currents in hippocampus slices

Molecular Cloning and Characterization of CALP/KChIP4, a Novel EF-hand Protein Interacting with Presenilin 2 and Voltage-gated Potassium Channel Subunit Kv4

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