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Transthyretin oligomers induce calcium influx via voltage-gated calcium channels


Hou, X and Parkington, HC and Coleman, HA and Mechler, A and Martin, LL and Aguilar, MI and Small, DH, Transthyretin oligomers induce calcium influx via voltage-gated calcium channels, Journal of Neurochemistry, 100, (2) pp. 446-457. ISSN 0022-3042 (2007) [Refereed Article]

DOI: doi:10.1111/j.1471-4159.2006.04210.x


The deposition of transthyretin (TTR) amyloid in the PNS is a major pathological feature of familial amyloidotic polyneuropathy. The aim of the present study was to examine whether TTR could disrupt cytoplasmic Ca 2+ homeostasis and to determine the role of TTR aggregation in this process. The aggregation of amyloidogenic TTR was examined by solution turbidity, dynamic light scattering and atomic force microscopy. A nucleation-dependent polymerization process was observed in which TTR formed low molecular weight aggregates (oligomers < 100 nm in diameter) before the appearance of mature fibrils. TTR rapidly induced an increase in the concentration of intracellular Ca2+ ([Ca2+]i) when applied to SH-SY5Y human neuroblastoma cells. The greatest effect on [Ca2+]i was induced by a preparation that contained the highest concentration of TTR oligomers. The TTR-induced increase in [Ca 2+]i was due to an influx of extracellular Ca 2+, mainly via L- and N-type voltage-gated calcium channels (VGCCs). These results suggest that increasing [Ca2+]i via VGCCs may be an important early event which contributes to TTR-induced cytotoxicity, and that TTR oligomers, rather than mature fibrils, may be the major cytotoxic form of TTR.

Item Details

Item Type:Refereed Article
Research Division:Biomedical and Clinical Sciences
Research Group:Neurosciences
Research Field:Neurosciences not elsewhere classified
Objective Division:Health
Objective Group:Clinical health
Objective Field:Clinical health not elsewhere classified
UTAS Author:Small, DH (Professor David Small)
ID Code:61098
Year Published:2007
Web of Science® Times Cited:49
Deposited By:Menzies Institute for Medical Research
Deposited On:2010-02-25
Last Modified:2010-05-03

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