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

Michno, Kinga; Knight, David; Campussano, Jorge M.; Hoef, Diana van de; Boulianne, Gabrielle L.

doi:10.1371/journal.pone.0006904

Cited by 25 publications

(14 citation statements)

References 54 publications

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“…Although there exists evidence in favour of FAD-PS mediated ‘ER calcium overload’ theory [ 37 ], the results presented here and several other studies show that the FAD-PS and to a lesser extent wild type PS lead to either attenuated or unchanged ER calcium [ 15 , 16 , 21 , 23 , 25 , 38 – 41 ]. The reason behind such discrepancies is not completely clear.…”

Section: Discussioncontrasting

confidence: 48%

Involvement of presenilin holoprotein upregulation in calcium dyshomeostasis of Alzheimer's disease

Honarnejad

Jung

Lammich

et al. 2013

J Cellular Molecular Medi

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Mutations in presenilins (PS1 and PS2) account for the vast majority of early onset familial Alzheimer's disease cases. Beside the well investigated role of presenilins as the catalytic unit in γ-secretase complex, their involvement in regulation of intracellular calcium homeostasis has recently come into more focus of Alzheimer's disease research. Here we report that the overexpression of PS1 full-length holoprotein forms, in particular familial Alzheimer's disease-causing forms of PS1, result in significantly attenuated calcium release from thapsigargin- and bradykinin-sensitive stores. Interestingly, treatment of HEK293 cells with γ-secretase inhibitors also leads to decreased amount of calcium release from endoplasmic reticulum (ER) accompanying elevated PS1 holoprotein levels. Similarly, the knockdown of PEN-2 which is associated with deficient PS1 endoproteolysis and accumulation of its holoprotein form also leads to decreased ER calcium release. Notably, we detected enhanced PS1 holoprotein levels also in postmortem brains of patients carrying familial Alzheimer's disease PS1 mutations. Taken together, the conditions in which the amount of full length PS1 holoprotein is increased result in reduction of calcium release from ER. Based on these results, we propose that the disturbed ER calcium homeostasis mediated by the elevation of PS1 holoprotein levels may be a contributing factor to the pathogenesis of Alzheimer's disease.

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Section: Discussioncontrasting

confidence: 48%

Involvement of presenilin holoprotein upregulation in calcium dyshomeostasis of Alzheimer's disease

Honarnejad

Jung

Lammich

et al. 2013

J Cellular Molecular Medi

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“…The neurogenesis and gliogenesis defects caused by PS1 deficiency also make primary cortical neurons derived from PS1 germline knockout embryos quite unsuitable for the study of PS1 function in the regulation of calcium homeostasis. Interestingly, genetic analysis in Drosophila showed that expression of FAD-linked mutant presenilin affects intracellular calcium stores and a loss of function mutant in calmodulin, an effector of intracellular calcium, can suppress presenilin-induced calcium deficits [57]. …”

Section: Presenilins In Calcium Homeostasismentioning

confidence: 99%

Presenilins in synaptic function and disease

Shen

2011

Trends in Molecular Medicine

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The presenilin genes harbor approximately 90% of mutations linked to early-onset familial Alzheimer’s disease (FAD), but how these mutations cause the disease is still being debated. Genetic analysis in Drosophila and mice demonstrate that presenilin plays essential roles in synaptic function, learning and memory, as well as neuronal survival in the adult brain, and the FAD-linked mutations alter the normal function of presenilin in these processes. Presenilin has also been reported to regulate calcium homeostasis of intracellular stores, and presynaptic presenilin controls neurotransmitter release and long-term potentiation through modulation of calcium release from intracellular stores. Here we highlight recent advances in deciphering the role of presenilin in synaptic function, calcium regulation and disease, and pose key questions for future studies.

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“…A DPS-null mutation has been reported to impair learning and memory, which, however, cannot be exclusively attributed to loss-of-function in the Notch pathway (26). In addition, DPS is also required for calcium homeostasis, the disruption of which may lead to cognitive deficits (27)(28)(29). Similarly to investigations in invertebrates, Notch has also been confirmed to interact with PSs and APP in mammals (30,31) and the expression of Notch 1 is increased in the brains of patients with AD (32).…”

Section: Introductionmentioning

confidence: 99%

Molecular cloning and characterization of presenilin gene in Bombyx mori

Zheng

Chao

Fan

et al. 2015

Molecular Medicine Reports

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Presenilin (PS), the catalytic core of the γ-secretase complex, is considered to be a causative protein of the early‑onset familial form of Alzheimer's disease. Aging is a risk factor for Alzheimer's disease and a number of genetic studies have utilized Bombyx mori (B. mori) as a model, making it possible to use B. mori to investigate Alzheimer's disease. However, the homologous gene of human PS in B. mori has remained to be elucidated. In the present study, the PS homologue gene in B. mori was identified and characterized, and six B. mori presenilin (BmPS) mRNA transcripts were generated by selecting multiple transcription start sites and/or alternative splice sites. The longest mRNA of BmPS (termed BmPS1) contains a 153 nt 5' untranslated region (UTR), a 1,440 nt open reading frame and a 1,063 nt 3' UTR. The predicted protein of BmPS1 consists of 479 amino acid residues and has two highly‑conserved aspartate residues, which form the catalytic core of aspartic proteases. It exhibits a sequence identity of ~44 and 51% with homologues in Homo sapiens and Drosophila melanogaster, respectively. However, the amino acid sequence of the BmPS loop region does not completely match between the two B. mori strains R13Q and Dazao. Genomic analysis revealed that B. mori had a single copy of the BmPS gene, which was composed of 14 exons. A total of four isoforms of BmPS (BmPS‑A, ‑B, ‑C and ‑D) owing to multiple transcriptional start sites and alternative splice sites were identified. The alternative splicing events occurring in the loop region improved the diversity of the BmPS protein and were detectable in all tissues, as determined using reverse transcription quantitative polymerase chain reaction (RT‑qPCR). Furthermore, the expression levels of BmPS in the brain at different developmental stages were detected using RT‑qPCR, and significantly higher expression levels of BmPS were found in the adult stage compared with those in the larval and pupal stages. The present study on BmPS provided insight into the pathogenesis of Alzheimer's disease and mechanisms of silkworm developmental regulation.

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

Cited by 25 publications

References 54 publications

Involvement of presenilin holoprotein upregulation in calcium dyshomeostasis of Alzheimer's disease

Involvement of presenilin holoprotein upregulation in calcium dyshomeostasis of Alzheimer's disease

Presenilins in synaptic function and disease

Molecular cloning and characterization of presenilin gene in Bombyx mori

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