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Only amyloidogenic inermediates of transthyretin induce apoptosis
Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
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2002 (Engelska)Ingår i: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 294, nr 2, s. 309-314Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

In diseases like Alzheimer's disease and familial amyloidotic polyneuropathy (FAP) amyloid deposits co-localize with areas of neurodegeneration. FAP is associated with mutations of the plasma protein transthyretin (TTR). We can here show an apoptotic effect of amyloidogenic mutants of TTR on a human neuroblastoma cell line. Toxicity could be blocked by catalase indicating a free oxygen radical dependent mechanism. The toxic effect was dependent on the state of aggregation and unexpectedly mature fibrils from FAP-patients who failed to exert an apoptotic response. Morphological studies revealed a correlation between toxicity and the presence of immature amyloid. Thus, we can show that toxicity is associated with early stages of fibril formation and propose that mature full-length fibrils represent an inert end stage, which might serve as a rescue mechanism. 

Ort, förlag, år, upplaga, sidor
Carolina Academic Press, 2002. Vol. 294, nr 2, s. 309-314
Nyckelord [en]
Amyloid, Transthyretin, Cytotoxicity, Apoptosis, Free radicals
Nationell ämneskategori
Cell- och molekylärbiologi Biokemi och molekylärbiologi
Identifikatorer
URN: urn:nbn:se:umu:diva-4476DOI: 10.1016/S0006-291X(02)00465-5ISI: 000176340800019PubMedID: 12051711OAI: oai:DiVA.org:umu-4476DiVA, id: diva2:143597
Tillgänglig från: 2005-04-08 Skapad: 2005-04-08 Senast uppdaterad: 2019-01-23Bibliografiskt granskad
Ingår i avhandling
1. Prefibrillar oligomeric Transthyretin mutants - amyloid conformation, toxicity and association with Serum amyloid P component
Öppna denna publikation i ny flik eller fönster >>Prefibrillar oligomeric Transthyretin mutants - amyloid conformation, toxicity and association with Serum amyloid P component
2005 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

Amyloidoses represent a heterogeneous group of diseases characterized by abnormal protein metabolism leading to extracellular deposition of fibrillar, proteinaceous amyloid in various tissues and organs of the body. To date more than 20 different proteins have been linked to diseases with amyloid depositions, of which Alzheimer’s disease and the prion-associated diseases are the most well known. Despite the origin of protein in the amyloid, the fibrils share some common biochemical and biophysical properties such as a diameter of 8-13 nm, a β-pleated sheet secondary structure packed in an ordered crystal-like way, Congo red and thioflavin binding with characteristic spectroscopic patterns and decoration of the fibrils with Serum amyloid P component and glycoseaminoglycans.

The plasma protein transthyretin (TTR) is associated with familial amyloidosis with polyneuropathy (FAP) and senile systemic amyloidosis (SSA). FAP is a lethal, autosomal inherited disorder caused by point mutations in the TTR-gene. More than 80 different mutations have been associated with amyloid formation and linked to FAP. The interpretation is that amino acid replacements at different sites of the polypeptide lead to reduced stability. Mutant TTR were constructed that have a strong tendency to self-aggregate under physiological conditions. The precipitates were shown to be amyloid by staining with thioflavin T and Congo red. As the mutants were sensitive to trypsin cleavage compared to plasma TTR, we suggest that the mutants represent amyloid precursors or that they may share structural properties with intermediates on a pathway leading to amyloid deposition. Monoclonal antibodies were generated that exclusively recognize the amyloidogenic folding of TTR providing direct biochemical evidence for a structural change in amyloidogenic intermediates. Two cryptic epitopes were mapped to a domain of TTR, where most mutations associated with amyloidosis occur and is proposed to be displaced at the initial phase of amyloid formation. Amyloidogenic intermediates of TTR were shown to induce a toxic, free radical dependent, response in cultured neuroblastoma cells. Morphological studies revealed a correlation between toxicity (apoptosis) and the presence of immature amyloid suggesting that mature full-length fibrils represent an inert end stage, which might serve as a rescue mechanism.

Serum amyloid P component (SAP) is a highly conserved plasma glycoprotein universally found associated with amyloid depositions independently of protein origin. SAP’s role in amyloid formation is contradictory since both inhibition and promotion of aggregation have been shown in the case of fibril formation from the Aβ peptide of Alzheimer’s disease. Amyloidogenic prefibrils of TTR were shown to bind SAP and no interference with aggregation was detected. SAP co-localize in patches with mutant TTR on the surface of neuroblastoma cells and prevent apoptosis induced by mutant TTR and Aβ peptide, while several other molecules known to decorate amyloid fibrils were without effect.

Förlag
s. 47
Serie
Umeå University medical dissertations, ISSN 0346-6612 ; 958
Nyckelord
Cell and molecular biology, Cell- och molekylärbiologi
Nationell ämneskategori
Biokemi och molekylärbiologi
Identifikatorer
urn:nbn:se:umu:diva-494 (URN)91-7305-862-9 (ISBN)
Disputation
2005-04-29, Major Groove, 6L, Inst f Molekylärbiologi, Umeå, 13:00
Opponent
Handledare
Tillgänglig från: 2005-04-08 Skapad: 2005-04-08 Senast uppdaterad: 2019-01-23Bibliografiskt granskad

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Andersson, KarinOlofsson, AndersLundgren, Erik

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Biochemical and Biophysical Research Communications - BBRC
Cell- och molekylärbiologiBiokemi och molekylärbiologi

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