Concentration-dependent effects of proteasomal inhibition on tau processing in a cellular model of tauopathy

Tadanori Hamano, Tania F. Gendron, Li Wen Ko, Shu Hui Yen

Research output: Contribution to journalArticle

15 Scopus citations

Abstract

Tauopathies are characterized by accumulation of filamentous tau aggregates. These aggregates can be recapitulated in transfectant M1C overproducing wild-type human brain tau 4R0N via the tetracycline off (TetOff) inducible expression mechanism. To determine the contribution of proteasomes to tau degradation and aggregation, we exposed M1C cells to epoxomicin (Epx; 2-50 nM) or MG132 (0.5 μM) on the 3rd or 4th day of a 5-day TetOff induction and demonstrated a reduction of proteasomal activity. Cultures treated with 2 nM Exp showed accumulation of full-length tau without affecting ubiquitin and β-catenin immunoblotting profiles. In contrast, cells treated with 10, 50 nM Epx or MG132 displayed changes in ubiquitin or β-catenin immunoblotting profiles and extensive tau degradation/truncation. The increase of tau degradation/truncation was accompanied with accumulation of oligomers and sarkosyl-insoluble aggregates of tau, augmented thioflavin-binding and activation of caspases and calpains. Truncated, oligomeric and sarkosyl-insoluble tau derivatives appeared with caspase-specific cleavage and their production was diminished when pretreated with a pan-caspase inhibitor. The results demonstrate (i) a dose-dependent, opposite effect of proteasome inhibition on tau processing, (ii) the participation of proteasome-dependent, ubiquitination-independent mechanisms in tau degradation and aggregation, and (iii) the promotion of tau aggregation by caspase-mediated tau degradation/truncation.

Original languageEnglish (US)
Pages (from-to)561-573
Number of pages13
JournalInternational Journal of Clinical and Experimental Pathology
Volume2
Issue number6
StatePublished - Jul 16 2009

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Keywords

  • Calpain
  • Caspase
  • Cell culture
  • Inducible transfectant
  • Proteasomal inhibition
  • Tau degradation and aggregation

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Histology

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