Presenilin mutants subvert chaperone function

Gething, Mary‐Jane

doi:10.1038/35000090

Cited by 11 publications

(4 citation statements)

References 14 publications

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“…It is becoming evident that protein folding in cells is not highly efficient (Schubert et al ., 2000), and that full‐time cooperation between proteolytic and chaperone systems in different cellular compartments provides a measure of immunity against toxic protein aggregates (Casagrande et al ., 2000; Gething, 2000; Travers et al ., 2000). Still, the cellular digestive tract can become overwhelmed or dysfunctional, resulting in manifestations of cellular indigestion including the formation of aggresomes and Russell bodies.…”

Section: Perspectivesmentioning

confidence: 99%

Aggresomes and Russell bodies

Kopito

Sitia²

2000

EMBO Reports

215

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All cells are equipped with a proteolytic apparatus that eliminates damaged, misfolded and incorrectly assembled proteins. The principal engine of cytoplasmic proteolysis, the 26S proteasome, requires that substrates be unfolded to gain access to the active site; consequently, it is relatively ineffective at degrading aggregated proteins. Cellular indigestion occurs when the production of aggregation-prone proteins exceeds the cell's (or organelle's) capacity to eliminate them. Cellular pathways that resolve this indigestion exist, but appear to have limited capacities. Russell bodies and aggresomes are manifestations of cellular indigestion in the endoplasmic reticulum and cytoplasmic compartments, respectively, and are often associated with disease.

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Section: Perspectivesmentioning

confidence: 99%

Aggresomes and Russell bodies

Kopito

Sitia²

2000

EMBO Reports

215

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“…Alzheimer's disease, prion-associated disorders, cystic fibrosis, etc. (53)(54)(55)(56). ERdj5 is expressed in the neuronal cells of the hippocampus (in situ data not shown), which is a site of neuron degeneration in the brains of Alzheimer's disease patients.…”

Section: Erdj5 Interacts With Bip Via the Dnaj Domain-hsp70mentioning

confidence: 99%

ERdj5, an Endoplasmic Reticulum (ER)-resident Protein Containing DnaJ and Thioredoxin Domains, Is Expressed in Secretory Cells or following ER Stress

Cunnea¹,

Miranda‐Vizuete²,

Bertoli³

et al. 2003

Journal of Biological Chemistry

178

139

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“…A simple interpretation would be that G o activated by low expression of N141I-PS2-like that by low expression of V642I-APP and NL-APP-only gives rise to NADPH oxidase activation, but that highly expressed N141I-PS2 may not only activate G o but also be able to act like a chaperone of G o in accession to XO, allowing activated G o to act on this enzyme. In support, chaperonelike function of PS has been postulated thus far (Gething, 2000). Alternatively, the effect of highly expressed N141I-PS2 on the action of G o may not be direct.…”

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confidence: 99%

Neurotoxic Mechanisms by Alzheimer’s Disease-Linked N141I Mutant Presenilin 2

Hashimoto

Niikura²,

Ito³

et al. 2002

The Journal of Pharmacology and Experimental Therapeutics

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Although it has been established that oxidative stress mediates cytotoxicity by familial Alzheimer's disease (FAD)-linked mutants of presenilin (PS)1 and that pertussis toxin inhibits cytotoxicity by FAD-linked N141I-PS2, it has not been determined whether oxidative stress is involved in cytotoxicity by N141I-PS2 or which pertussis toxin-sensitive proteins mediate the cytotoxicity. Here we report that low expression of N141I-PS2 caused neuronal cell death, whereas low expression of wildtype PS2 did not. Cytotoxicities by low and high expression of N141I-PS2 occurred through dissimilar mechanisms: the former cytotoxicity was blocked by a cell-permeable caspase inhibitor, and the latter was not. Since both mechanisms were sensitive to a cell-permeable antioxidant, we examined potential sources of reactive oxygen species in each mechanism, and found that the caspase inhibitor-sensitive neurotoxicity by N141I-PS2 was likely through NADPH oxidase and the caspase inhibitor-resistant neurotoxicity by N141I-PS2 through xanthine oxidase. Pertussis toxin greatly suppressed both toxic mechanisms by N141I-PS2, and only G␣ o , a neuron-enriched pertussis toxin-sensitive G protein, was involved in both mechanisms. We therefore conclude that N141I-PS2 is capable of triggering multiple neurotoxic mechanisms, which can be inhibited by the combination of clinically usable inhibitors of NADPH oxidase and xanthine oxidase. This study thus provides a novel insight into the therapeutic intervention of PS2 mutant-associated FAD.Familial Alzheimer's disease (FAD) is caused by mutations in amyloid precursor protein (APP), presenilin (PS)1, and PS2 (Shastry and Giblin, 1999). However, how these mutant genes cause neural death, the central abnormality in Alzheimer's disease (AD), has been little understood. A clue is the finding that expression of FAD mutant APP and PS genes causes neural cell death in cultures

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Presenilin mutants subvert chaperone function

Cited by 11 publications

References 14 publications

Aggresomes and Russell bodies

Aggresomes and Russell bodies

ERdj5, an Endoplasmic Reticulum (ER)-resident Protein Containing DnaJ and Thioredoxin Domains, Is Expressed in Secretory Cells or following ER Stress

Neurotoxic Mechanisms by Alzheimer’s Disease-Linked N141I Mutant Presenilin 2

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