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Inhibition of TTR aggregation-induced cell death: a new role for serum amyloid P component
Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
2013 (engelsk)Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, nr 2Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

BACKGROUND: Serum amyloid P component (SAP) is a glycoprotein that is universally found associated with different types of amyloid deposits. It has been suggested that it stabilizes amyloid fibrils and therefore protects them from proteolytic degradation.

METHODOLOGY/PRINCIPAL FINDINGS: In this paper, we show that SAP binds not only to mature amyloid fibrils but also to early aggregates of amyloidogenic mutants of the plasma protein transthyretin (TTR). It does not inhibit fibril formation of TTR mutants, which spontaneously form amyloid in vitro at physiological pH. We found that SAP prevents cell death induced by mutant TTR, while several other molecules that are also known to decorate amyloid fibrils do not have such effect. Using a Drosophila model for TTR-associated amyloidosis, we found a new role for SAP as a protective factor in inhibition of TTR-induced toxicity. Overexpression of mutated TTR leads to a neurological phenotype with changes in wing posture. SAP-transgenic flies were crossed with mutated TTR-expressing flies and the results clearly confirmed a protective effect of SAP on TTR-induced phenotype, with an almost complete reduction in abnormal wing posture. Furthermore, we found in vivo that binding of SAP to mutated TTR counteracts the otherwise detrimental effects of aggregation of amyloidogenic TTR on retinal structure.

CONCLUSIONS/SIGNIFICANCE: Together, these two approaches firmly establish the protective effect of SAP on TTR-induced cell death and degenerative phenotypes, and suggest a novel role for SAP through which the toxicity of early amyloidogenic aggregates is attenuated.

sted, utgiver, år, opplag, sider
2013. Vol. 8, nr 2
Emneord [en]
Serum amyloid P component, transthyretin, familial amyloid polyneuropathy, cell death, neuroblastoma, drosophila
HSV kategori
Forskningsprogram
molekylärbiologi; medicinsk cellbiologi
Identifikatorer
URN: urn:nbn:se:umu:diva-65622DOI: 10.1371/journal.pone.0055766ISI: 000314691100067OAI: oai:DiVA.org:umu-65622DiVA, id: diva2:604329
Merknad

Epub 2013 Feb 4.

Tilgjengelig fra: 2013-02-09 Laget: 2013-02-09 Sist oppdatert: 2018-06-08bibliografisk kontrollert

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