Interfering with Apoptosis: Ca
            <sup>2+</sup>
            -Binding Protein ALG-2 and Alzheimer's Disease Gene
            <i>ALG-3</i>

Vito, Pasquale; Lacaná, Emanuela; D’Adamio, Luciano

doi:10.1126/science.271.5248.521

Cited by 469 publications

(323 citation statements)

References 50 publications

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“…Presenilin also affects β-catenin signalling which then helps regulate the cell cycle [2], a process that could be disrupted by PS over expression or mutation. Finally, under or over-expressed or mutant presenilins inhibit the cell cycle [15,16], increase cells' sensitivity to apoptosis [6,10,43,44,48] and, in transgenic mice, results in age-related neurodegeneration [3,36] and reduced neurogenesis [9,45,46,51]. All of these effects would be a natural consequence of aneuploidy activating the mitotic cell cycle checkpoint.…”

Section: Discussionmentioning

confidence: 99%

Alzheimer's presenilin 1 causes chromosome missegregation and aneuploidy

Boeras

Granic

Padmanabhan

et al. 2008

Neurobiology of Aging

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Mutations in the presenilin 1 gene cause most early-onset familial Alzheimer's disease (FAD). Here we report that a defect in the cell cycle-improper chromosome segregation-can be caused by abnormal presenilin function and therefore may contribute to AD pathogenesis. Specifically we find that either over-expression or FAD mutation in presenilin 1 (M146L and M146V) leads to chromosome missegregation and aneuploidy in vivo and in vitro: 1) Up to 20% of lymphocytes and neurons of FAD-PS-1 transgenic and knockin mice are aneuploid by metaphase chromosome analysis and in situ hybridization, 2) Transiently transfected human cells over-expressing normal or mutant PS-1 develop similar aneuploidy within 48 hours, including trisomy 21. 3) Mitotic spindles in the PS-1 transfected cells contain abnormal microtubule arrays and lagging chromosomes. Several mechanisms by which chromosome missegregation induced by presenilin may contribute to Alzheimer's disease are discussed.

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Section: Discussionmentioning

confidence: 99%

Alzheimer's presenilin 1 causes chromosome missegregation and aneuploidy

Boeras

Granic

Padmanabhan

et al. 2008

Neurobiology of Aging

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“…Calcium is thought to play a role in many model systems of apoptosis (26,27). For example, in thymocytes, an increase in intracellularcalciumisthoughttoactivateacalcium/magnesiumdependent endonuclease which leads to DNA fragmentation, and in many cells, elevation of intracellular calcium with the use of ionophores and/or thapsigargin can induce apoptosis (22,23,26,28).…”

Section: Discussionmentioning

confidence: 99%

Appearance of Phosphatidylserine on Apoptotic Cells Requires Calcium-mediated Nonspecific Flip-Flop and Is Enhanced by Loss of the Aminophospholipid Translocase

Bratton

Fadok

Richter

et al. 1997

Journal of Biological Chemistry

418

294

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Phosphatidylserine (PS), ordinarily sequestered in the plasma membrane inner leaflet, appears in the outer leaflet during apoptosis, where it triggers non-inflammatory phagocytic recognition of the apoptotic cell. The mechanism of PS appearance during apoptosis is not well understood but has been associated with loss of aminophospholipid translocase activity and nonspecific flip-flop of phospholipids of various classes. The human leukemic cell line HL-60, the T cell line Jurkat, and peripheral blood neutrophils, undergoing apoptosis induced either with UV irradiation or anti-Fas antibody, were probed in the cytofluorograph for (i) surface PS using fluorescein isothiocyanate-labeled annexin V, (ii) PS uptake by the aminophospholipid translocase using [6-[(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino] caproyl] (NBD)-labeled PS, (iii) nonspecific uptake of phospholipids (as a measure of transbilayer flip-flop) using NBDlabeled phosphatidylcholine, and (iv) the appearance of hypodiploid DNA. In all three types of cells undergoing apoptosis, the appearance of PS followed loss of aminophospholipid translocase and was accompanied by nonspecific phospholipid flip-flop. Importantly, however, in the absence of extracellular calcium, the appearance of PS was completely inhibited despite DNA fragmentation and loss of aminophospholipid translocase activity, the latter demonstrating that loss of the translocase is insufficient for PS appearance during apoptosis. Furthermore, while both the appearance of PS and nonspecific phospholipid uptake demonstrated identical extracellular calcium requirements with an ED 50 of nearly 100 M, the magnitude of PS appearance depended on the level of aminophospholipid translocase activity. Taken together, the data strongly suggest that while nonspecific flip-flop is the driving event for PS appearance in the plasma membrane outer leaflet, aminophospholipid translocase activity ultimately modulates its appearance.The appearance of phosphatidylserine in the outer leaflet of the plasma membrane appears to be a universal phenomenon in cells undergoing apoptosis, or programmed cell death (1). Importantly, outer leaflet PS likely serves as a signal in tissues for the noninflammatory engulfment of apoptotic cells (Ref. 2 and see "Discussion"), a distinctly different response than the pro-inflammatory events following tissue necrosis. While phosphatidylserine (PS) 1 is actively transported from the outer to the inner leaflet by the aminophospholipid translocase (3-5), the mechanism(s) by which PS appears in apoptosis is not well understood. Verhoven et al. (3) reported that PS appearance was accompanied by both loss of aminophospholipid translocase activity and enhanced nonspecific transbilayer movement of phospholipids, perhaps due to activation of a "scramblase." Hence, they proposed that PS may become detectable in the outer leaflet due to the combination of these two events. However, to date, the relative contribution of these two events has not been clarified. Additionally, it is not known what role...

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“…Abnormal efflux of the ion into cellular compartments (Nicotera et al, 1992) causes activation of a number of Ca 2ϩ -dependent degradative processes detrimental to the cell. Interestingly, one of the newly discovered "apoptosis-linked genes" encodes a Ca 2ϩ binding protein and shows partial homology to the FAD gene STM2 (Vito et al, 1996).…”

Section: Discussionmentioning

confidence: 99%

Melatonin Prevents Death of Neuroblastoma Cells Exposed to the Alzheimer Amyloid Peptide

et al. 1997

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Studies from several laboratories have generated evidence suggesting that oxidative stress is involved in the pathogenesis of Alzheimer's disease (AD). The finding that the amyloid ␤ protein (A␤) has neurotoxic properties and that such effects are, in part, mediated by free radicals has provided insights into mechanisms of cell death in AD and an avenue to explore new therapeutic approaches. In this study we demonstrate that melatonin, a pineal hormone with recently established antioxidant properties, is remarkably effective in preventing death of cultured neuroblastoma cells as well as oxidative damage and intracellular Ca 2ϩ increases induced by a cytotoxic fragment of A␤. The effects of melatonin were extremely reproducible and corroborated by multiple quantitative methods, including cell viability studies by confocal laser microscopy, electron microscopy, and measurements of intracellular calcium levels. The importance of this finding is that, in contrast to conventional antioxidants, melatonin has a proposed physiological role in the aging process. Secretion levels of this hormone are decreased in aging and more severely reduced in AD. The reported phenomenon may be of therapeutic relevance in AD.

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Interfering with Apoptosis: Ca ²⁺ -Binding Protein ALG-2 and Alzheimer's Disease Gene ALG-3

Cited by 469 publications

References 50 publications

Alzheimer's presenilin 1 causes chromosome missegregation and aneuploidy

Alzheimer's presenilin 1 causes chromosome missegregation and aneuploidy

Appearance of Phosphatidylserine on Apoptotic Cells Requires Calcium-mediated Nonspecific Flip-Flop and Is Enhanced by Loss of the Aminophospholipid Translocase

Melatonin Prevents Death of Neuroblastoma Cells Exposed to the Alzheimer Amyloid Peptide

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Interfering with Apoptosis: Ca 2+ -Binding Protein ALG-2 and Alzheimer's Disease Gene ALG-3

Cited by 469 publications

References 50 publications

Alzheimer's presenilin 1 causes chromosome missegregation and aneuploidy

Alzheimer's presenilin 1 causes chromosome missegregation and aneuploidy

Appearance of Phosphatidylserine on Apoptotic Cells Requires Calcium-mediated Nonspecific Flip-Flop and Is Enhanced by Loss of the Aminophospholipid Translocase

Melatonin Prevents Death of Neuroblastoma Cells Exposed to the Alzheimer Amyloid Peptide

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Interfering with Apoptosis: Ca ²⁺ -Binding Protein ALG-2 and Alzheimer's Disease Gene ALG-3