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Transthyretin oligomers induce calcium influx via voltage-gated calcium channels
journal contribution
posted on 2023-05-17, 01:33 authored by Hou, X, Parkington, HC, Coleman, HA, Mechler, A, Martin, LL, Aguilar, MI, David SmallDavid SmallThe 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.
History
Publication title
Journal of NeurochemistryVolume
100Pagination
446-457ISSN
0022-3042Department/School
Menzies Institute for Medical ResearchPublisher
Blackwell Publishing LtdPlace of publication
9600 Garsington Rd, Oxford, England, Oxon, Ox4 2DgRepository Status
- Restricted