Alterations of chaperone protein expression in presenilin mutant neurons in response to glutamate excitotoxicity

Maezawa, Izumi; Wang, Baiping; Hu, Qubai; Martin, George M.; Jin, Lee Way; Oshima, Junko

doi:10.1046/j.1440-1827.2002.01398.x

Cited by 4 publications

(4 citation statements)

References 22 publications

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“…Cam activity has previously been implicated in regulating the stability and proteolysis of other integral membrane proteins [54]. Interestingly, others have shown that calmodulin RNA levels can be impacted by FAD- Psn expression [55]. We have been unable to detect any effect of loss of a single Cam allele on the FAD-presenilin protein levels (Figure S1).…”

Section: Discussionmentioning

confidence: 70%

Intracellular Calcium Deficits in Drosophila Cholinergic Neurons Expressing Wild Type or FAD-Mutant Presenilin

et al. 2009

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Much of our current understanding about neurodegenerative diseases can be attributed to the study of inherited forms of these disorders. For example, mutations in the presenilin 1 and 2 genes have been linked to early onset familial forms of Alzheimer's disease (FAD). Using the Drosophila central nervous system as a model we have investigated the role of presenilin in one of the earliest cellular defects associated with Alzheimer's disease, intracellular calcium deregulation. We show that expression of either wild type or FAD-mutant presenilin in Drosophila CNS neurons has no impact on resting calcium levels but does give rise to deficits in intracellular calcium stores. Furthermore, we show that a loss-of-function mutation in calmodulin, a key regulator of intracellular calcium, can suppress presenilin-induced deficits in calcium stores. Our data support a model whereby presenilin plays a role in regulating intracellular calcium stores and demonstrate that Drosophila can be used to study the link between presenilin and calcium deregulation.

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Section: Discussionmentioning

confidence: 70%

Intracellular Calcium Deficits in Drosophila Cholinergic Neurons Expressing Wild Type or FAD-Mutant Presenilin

et al. 2009

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“…56,57 As with up-regulated genes, several observations overlap with the known differences in other neurodegenerative diseases.…”

Section: Scgt1/gt1 Hypothalamic Cell Gene Regulationmentioning

confidence: 90%

Cell Line Dependent RNA Expression Profiles of Prion-infected Mouse Neuronal Cells

Greenwood

Horsch

Stengel

et al. 2005

Journal of Molecular Biology

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“…Thus far, neuronal NPM1 has been investigated in two independent studies in the context of excitotoxicity, a process that leads to the necrotic death of neurons. These studies showed that NPM1 mRNA is decreased in glutamate-treated cortical cultures from PS1 M146V mutant transgenic mice (39) and that its protein is down-regulated in degenerating neurons of the rat hippocampal CA1 region, as well as primary neuronal cultures following kainic acid treatment (13). We report, however, that NPM1 expression is increased in both the R6/2 transgenic and 3-NP chemical mouse models of Huntington's disease.…”

Section: Discussionmentioning

confidence: 57%

Regulation of Neuronal Survival by Nucleophosmin 1 (NPM1) Is Dependent on Its Expression Level, Subcellular Localization, and Oligomerization Status

Pfister

D’Mello

2016

Journal of Biological Chemistry

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NPM1 (nucleophosmin 1) is a nucleolar phosphoprotein that regulates many cellular processes, including ribosome biogenesis, proliferation, and genomic integrity. Although its role in proliferating cell types and tissues has been extensively investigated, little is known about its function in neurons and in the brain where it is highly expressed. We report that NPM1 protein expression is increased selectively in the striatum in both the R6/2 transgenic and 3-nitropropionic acid-injected mouse models of Huntington's disease. Examination of the effect of ectopic expression on cultured neurons revealed that increasing NPM1 is toxic to otherwise healthy cerebellar granule and cortical neurons. Toxicity is dependent on its cytoplasmic localization and oligomerization status. Forced retention of NPM1 in the nucleus, as well as inhibiting its ability to oligomerize, not only neutralizes NPM1 toxicity but also renders it protective against apoptosis. Although not blocked by pharmacological inhibition of the pro-apoptotic molecules, JNK, glycogen synthase kinase 3 beta, or caspases, toxicity is blocked by compounds targeting cyclin-dependent kinases (CDKs), as well as by dominant-negative forms of CDK1 and CDK2 and the pan-CDK inhibitor, p21Cip1/Waf1 . Although induced in in vivo Huntington's disease models, NPM1 protein levels are unchanged in cultured cerebellar granule and cortical neurons induced to die by low potassium or homocysteic acid treatment, respectively. Moreover, and counterintuitively, knockdown of its expression or inhibition of endogenous NPM1 oligomerization in these cultured neurons is toxic. Taken together, our study suggests that although neurons need NPM1 for survival, an increase in its expression beyond physiological levels and its translocation to the cytoplasm leads to death through abortive cell cycle induction.NPM1, also known as B23, is an abundant, ubiquitously expressed, and evolutionarily conserved non-ribosomal nucleolar phosphoprotein (1, 2). It is one of three members of the nucleophosmin/nucleoplasmin family of proteins, the other two being NPM2 and NPM3. NPM1 is an important regulator of a variety of cellular processes including centrosome duplication, genomic stability, cell proliferation, and the response to genotoxic stress. Inactivation of the NPM1 gene in mice causes death at midgestation, indicating its requirement for normal development. Fibroblasts cultured from NPM1 knock-out mice display genomic instability and reduced growth and cell proliferation (3). Other studies have shown that NPM1 can shuttle between the nucleolus and the nucleoplasm and from the nucleus to the cytoplasm. Nuclear export is believed to be required for cellular proliferation (4, 5). Mutations of NPM1 are associated with cancers and are responsible for approximately a third of cases of acute myeloid leukemia in humans (3, 6 -8). These mutations, which result in an altered C terminus containing an addition of a nuclear export signal, have been reported to aberrantly localize NPM1 to the cytoplasm (8). Ove...

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Alterations of chaperone protein expression in presenilin mutant neurons in response to glutamate excitotoxicity

Cited by 4 publications

References 22 publications

Intracellular Calcium Deficits in Drosophila Cholinergic Neurons Expressing Wild Type or FAD-Mutant Presenilin

Intracellular Calcium Deficits in Drosophila Cholinergic Neurons Expressing Wild Type or FAD-Mutant Presenilin

Cell Line Dependent RNA Expression Profiles of Prion-infected Mouse Neuronal Cells

Regulation of Neuronal Survival by Nucleophosmin 1 (NPM1) Is Dependent on Its Expression Level, Subcellular Localization, and Oligomerization Status

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