Presenilin-1 Holoprotein is an Interacting Partner of Sarco Endoplasmic Reticulum Calcium-ATPase and Confers Resistance to Endoplasmic Reticulum Stress

Jin, Haifeng; Sanjo, Nobuo; Uchihara, Toshiki; Watabe, Kazuhiko; George-Hyslop, Peter St; Fraser, Paul E.; Mizusawa, Hidehiro

doi:10.3233/jad-2010-1360

Cited by 29 publications

(16 citation statements)

References 48 publications

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“…As was previously reported, PSEN1 was chiefly involved with the development and aggravation of Alzhemier's disease, human cancers (eg, colorectal cancer, bladder cancer, and liver cancer) and T‐cell acute lymphoblastic leukemia . Besides, the raised N1IC level within drug‐resistant cells was associated with incrementalγ‐secretase activity, and PSEN1 has been verified as the downstream gene of miR‐193a‐3p within bladder cancer .…”

Section: Discussionsupporting

confidence: 60%

The LncRNA H19/miR‐193a‐3p axis modifies the radio‐resistance and chemotherapeutic tolerance of hepatocellular carcinoma cells by targeting PSEN1

Liu

et al. 2018

J of Cellular Biochemistry

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This study was designated to verify if the lncRNA H19/miR-193a-3p axis would play a regulatory role in the radio-/chemo-resistances of HCC cells through targeting PSEN1. Within the study, five human HCC cell lines were prepared, including Bel-7402, HepG2, Hep3b, QGY-7703, and SMMC-7721. Moreover, docetaxel (DT), paclitaxel (Pt), vinorelbine (Vb), and 5-fluorouracil (5-Fu) were managed as the chemo-therapeutics, and single-dose X-rays were performed as radio-therapies. Besides, lncRNA H19 and miR-193a-3p were detected by qRT-PCR and Western blot were implemented to quantify the expressional levels of PSEN1, Ku80, γ-H2AX, and RAD51. Luciferase reporter gene assay was advanced to verify the targeted relationship between lncRNA H19 and miR-193a-3p. As a consequence, QGY-7703 and Bel-7402 were, respectively, the most radiation-sensitive and radiation-proof cell lines, and Bel-7402 was associated with the highest resistances to DT, Pt, Vb, and 5-FU. The restrained lncRNA H19 and over-expressed miR-193a-3p expressions tended to significantly elevate the survival rate and proliferation of Bel-7402 cells, when they were exposed to radiation and subject to chemo-therapies. The lncRNA H19 was also found to directly target miR-193a-3p in inducing the HCC development. PSEN1 appeared to be subject to the modification of lncRNA H19 and miR-193a-3p in its acting on the survival rates and proliferative abilities of HCC cells. The lncRNA H19/miR-193a-3p/PSEN1 axis could be regarded as the treatment targets for HCC, so as to further improve the treatment efficacy of chemo- and radio-therapies for HCC.

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Section: Discussionsupporting

confidence: 60%

The LncRNA H19/miR‐193a‐3p axis modifies the radio‐resistance and chemotherapeutic tolerance of hepatocellular carcinoma cells by targeting PSEN1

Liu

et al. 2018

J of Cellular Biochemistry

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“…Consistent with this, presenilins are required for Ca 2+ influx into cells through "store-operated" Ca 2+ (SOC) channels located in the plasma membrane ("capacitative calcium entry" [CCE]), which require microdomains containing both an active sarcoplasmic/endoplasmic reticulum calcium ATPase (SER-CA) -a protein associated with PS1 [119,120] -and neighboring mitochondria [121]. In cells with FADlinked mutations, ER [Ca 2+ ] was increased [117,122] and CCE was inhibited [122][123][124], with downstream effects on AβPP processing and Aβ production [123][124][125].…”

Section: Ea Schon and E Area-gomez / Mam Dysfunction In Ad Pathogementioning

confidence: 88%

Is Alzheimer's Disease a Disorder of Mitochondria-Associated Membranes?

Schon

Area‐Gómez

2010

JAD

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Abstract. The subcellular localization of presenilin-1 (PS1) and presenilin-2 (PS2), two proteins that, when mutated, cause familial Alzheimer's disease (AD), is controversial. We have discovered that mitochondria-associated membranes (MAM) -a specialized subcompartment of the endoplasmic reticulum (ER) involved in lipid metabolism and calcium homeostasis that physically connects ER to mitochondria -is the predominant subcellular location for PS1 and PS2, and for γ-secretase activity. We hypothesize that presenilins play a role in maintaining MAM function, and that not only altered amyloid-β levels and hyperphosphorylated tau, but also many other features of AD (e.g., altered phospholipid and cholesterol metabolism, aberrant calcium homeostasis, and abnormal mitochondrial dynamics) result from compromised MAM function. The localization of presenilins and γ-secretase in MAM may help reconcile disparate ideas regarding the pathogenesis of AD, under a unifying hypothesis that could explain many features of both sporadic and familial AD, thereby taking AD research in a new and fruitful direction.Keywords: Alzheimer's disease, calcium, cholesterol, endoplasmic reticulum (ER), mitochondria, mitochondria-associated membranes (MAM), phospholipids ALZHEIMER'S DISEASEAlzheimer's disease (AD), the most common late onset neurodegenerative dementing disorder, is characterized by progressive neuronal loss, especially in the hippocampus and cortex [1]. The two main histopathological hallmarks of AD are the accumulation of extracellular neuritic plaques, containing amyloid-β (Aβ), and of neurofibrillary tangles, consisting mainly of hyperphosphorylated forms of the microtubule-associated protein tau [1]. Most AD patients are sporadic (SAD), but three genes have been associated with the familial form (FAD): amyloid-β protein precursor (AβPP), presenilin-1 (PS1), and presenilin-2 (PS2). Clinically, FAD is similar to SAD but has earlier onset. Presenilins are components of the γ-secretase complex (also containing APH1, nicastrin, and PEN2) that, together with β-secretase, processes AβPP to produce Aβ [1]. In the mainstream view, both SAD and FAD arise when AβPP is processed to Aβ, which accumulates in extracellular plaques. Aβ is toxic to cells and the resulting stress promotes tau hyperphosphorylation, leading to the tangles. The overall process has been called the "amyloid cascade" hypothesis [2,3]. This hypothesis reconciles findings from different approaches to the disease and has served as the basis for many key experiments in vivo and in vitro. However, certain questions that are central to understanding the pathogenesis of AD and the processing of Aβ remain unsolved.The first question concerns features of AD that are not obviously linked to plaque or tangle formation. While plaques and tangles are hallmarks of the disease, other apparently unrelated laboratory abnormali-

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“…The nature of the interaction between PS1 and ER stress has yet to be fully elucidated, although it is known that PS1 and the SERCA calcium pump physically interact with one another 80 . As discussed, disordered calcium homeostasis is a potent cause of ER stress and much evidence suggests that calcium signalling is perturbed in…”

Section: Alzheimer's Diseasementioning

confidence: 99%

Endoplasmic reticulum dysfunction in neurological disease

Roussel

Kruppa

Miranda

et al. 2013

The Lancet Neurology

404

310

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Endoplasmic reticulum (ER) dysfunction is important in the pathogenesis of many neurological diseases. In this review, we examine the evidence for ER dysfunction in a range of neurological conditions including cerebral ischaemia, sleep apnoea, Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, the prion diseases and Familial Encephalopathy with Neuroserpin Inclusion Bodies (FENIB). Protein misfolding in the endoplasmic reticulum initiates a well-studied 'Unfolded Protein Response' in energy-starved neurones during stroke that is relevant to the toxicity of reperfusion. The toxic peptide Aβ induces 'ER stress' in Alzheimer's disease leading to activation of similar pathways, while the accumulation of polymeric neuroserpin in the neuronal ER triggers a poorly understood 'ER overload response'. In other neurological disorders such as Parkinson's and Huntington's diseases ER dysfunction is well recognised but the mechanisms for this are less clear. By targeting components of these signalling responses, it may prove possible to ameliorate their toxic effects and treat a range of neurodegenerative conditions. 1 IMPLICATIONS OF ENDOPLASMIC RETICULUM DYSFUNCTION

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Presenilin-1 Holoprotein is an Interacting Partner of Sarco Endoplasmic Reticulum Calcium-ATPase and Confers Resistance to Endoplasmic Reticulum Stress

Cited by 29 publications

References 48 publications

The LncRNA H19/miR‐193a‐3p axis modifies the radio‐resistance and chemotherapeutic tolerance of hepatocellular carcinoma cells by targeting PSEN1

The LncRNA H19/miR‐193a‐3p axis modifies the radio‐resistance and chemotherapeutic tolerance of hepatocellular carcinoma cells by targeting PSEN1

Is Alzheimer's Disease a Disorder of Mitochondria-Associated Membranes?

Endoplasmic reticulum dysfunction in neurological disease

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