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The BRICHOS domain ...
The BRICHOS domain of Bri2 inhibits islet amyloid polypeptide (IAPP) fibril formation and toxicity in human beta cells
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- Oskarsson, Marie E. (författare)
- Uppsala universitet,Institutionen för medicinsk cellbiologi,Gunilla Westermark
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Hermansson, Erik (författare)
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- Wang, Ye (författare)
- Uppsala universitet,Institutionen för medicinsk cellbiologi,Gunilla Westermark
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- Welsh, Nils (författare)
- Uppsala universitet,Institutionen för medicinsk cellbiologi
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- Presto, Jenny (författare)
- Karolinska Institutet
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- Johansson, Jan (författare)
- Karolinska Institutet
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- Westermark, Gunilla (författare)
- Uppsala universitet,Institutionen för medicinsk cellbiologi
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(creator_code:org_t)
- 2018-03-05
- 2018
- Engelska.
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 115:12, s. E2752-E2761
- Relaterad länk:
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https://www.pnas.org...
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https://urn.kb.se/re...
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https://doi.org/10.1...
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http://kipublication...
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Abstract
Ämnesord
Stäng
- Aggregation of islet amyloid polypeptide (IAPP) into amyloid fibrils in islets of Langerhans is associated with type 2 diabetes, and formation of toxic IAPP species is believed to contribute to the loss of insulin-producing beta cells. The BRICHOS domain of integral membrane protein 2B (Bri2), a transmembrane protein expressed in several peripheral tissues and in the brain, has recently been shown to prevent fibril formation and toxicity of Aβ42, an amyloid-forming peptide in Alzheimer disease. In this study, we demonstrate expression of Bri2 in human islets and in the human beta-cell line EndoC-βH1. Bri2 colocalizes with IAPP intracellularly and is present in amyloid deposits in patients with type 2 diabetes. The BRICHOS domain of Bri2 effectively inhibits fibril formation in vitro and instead redirects IAPP into formation of amorphous aggregates. Reduction of endogenous Bri2 in EndoC-βH1 cells with siRNA increases sensitivity to metabolic stress leading to cell death while a concomitant overexpression of Bri2 BRICHOS is protective. Also, coexpression of IAPP and Bri2 BRICHOS in lateral ventral neurons of Drosophila melanogaster results in an increased cell survival. IAPP is considered to be the most amyloidogenic peptide known, and described findings identify Bri2, or in particular its BRICHOS domain, as an important potential endogenous inhibitor of IAPP aggregation and toxicity, with the potential to be a possible target for the treatment of type 2 diabetes.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)
- NATURVETENSKAP -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)
Nyckelord
- Bri2
- BRICHOS
- chaperone
- IAPP
- amyloid
- islet amyloid
- beta cells
- type 2 diabetes
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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