Alteration in calcium channel properties is responsible for the neurotoxic action of a familial frontotemporal dementia tau mutation

Katsutoshi Furukawa, Yue Wang, Pamela J. Yao, Weiming Fu, Mark P. Mattson, Yasuto Itoyama, Hiroshi Onodera, Ian D'Souza, Parvone H. Poorkaj, Thomas D. Bird, Gerard D. Schellenberg

Research output: Contribution to journalArticle

51 Citations (Scopus)

Abstract

Tau, a microtubule binding protein, is not only a major component of neurofibrillary tangles in Alzheimer's disease, but also a causative gene for hereditary frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). We show here that an FTDP-17 tau mutation (V337M) in SH-SY5Y cells reduces microtubule polymerization, increases voltage-dependent calcium current (ICa) density, and decreases ICa rundown. The reduced rundown of ICa by V337M was significantly inhibited by nifedipine (L-type Ca channel blocker), whereas ω-conotoxin GVIA (N-type Ca channel blocker) showed smaller effects, indicating that tau mutations affect L-type calcium channel activity. The depolarization-induced increase in intracellular calcium was also significantly augmented by the V337M tau mutation. Treatment with a microtubule polymerizing agent (taxol), an adenylyl cyclase inhibitor, or a protein kinase A (PKA) inhibitor, counteracted the effects of mutant tau on ICa. Taxol also attenuated the Ca2+ response to depolarization in cells expressing mutant tau. Apoptosis in SH-SY5Y cells induced by serum deprivation was exacerbated by the V337M mutation, and nifedipine, taxol, and a PKA inhibitor significantly protected cells against apoptosis. Our results indicate that a tau mutation which decreases its microtubule-binding ability augments calcium influx by depolymerizing microtubules and activating adenylyl cyclase and PKA.

Original languageEnglish
Pages (from-to)427-436
Number of pages10
JournalJournal of Neurochemistry
Volume87
Issue number2
DOIs
Publication statusPublished - 2003 Oct

Keywords

  • Calcium
  • Channel
  • Frontotemporal dementia and parkinsonism linked to chromosome 17
  • Microtubule
  • Neurodegeneration
  • Tau

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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