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Int J Clin Exp Pathol 2(6),561-573;2009
Original Article
Concentration-dependent Effects of Proteasomal Inhibition on tau Processing in a
Cellular Model of Tauopathy
Tadanori Hamano, Tania F. Gendron, Li-wen Ko and Shu-Hui Yen
Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, FL
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.
(IJCEP905001).
Key words: tau degradation and aggregation, inducible transfectant, cell culture, proteasomal inhibition, caspase, calpain
Full text PDF
Address all correspondence to: Shu-Hui Yen, Ph.D., Department of Neuroscience, Mayo Clinic Jacksonville, 4500 San Pablo Road,
Jacksonville, FL 32224. Tel: 1-904-953-1066; Fax: 1-904-953-7117; Email: Yen. Shu-Hui@mayo.edu
Original Article
Concentration-dependent Effects of Proteasomal Inhibition on tau Processing in a
Cellular Model of Tauopathy
Tadanori Hamano, Tania F. Gendron, Li-wen Ko and Shu-Hui Yen
Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, FL
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.
(IJCEP905001).
Key words: tau degradation and aggregation, inducible transfectant, cell culture, proteasomal inhibition, caspase, calpain
Full text PDF
Address all correspondence to: Shu-Hui Yen, Ph.D., Department of Neuroscience, Mayo Clinic Jacksonville, 4500 San Pablo Road,
Jacksonville, FL 32224. Tel: 1-904-953-1066; Fax: 1-904-953-7117; Email: Yen. Shu-Hui@mayo.edu
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