CALCINEURIN INHIBITION PREVENTS CALPAIN-MEDIATED PROTEOLYSIS OF TAU IN DIFFERENTIATED PC12 CELLS

The effects of calcium influx on tau levels and phosphorylation were e xamined in differentiated PC12 cells. Maitotoxin-induced calcium influ x resulted in time- and concentration-dependent tau dephosphorylation and degradation. Incubation of PC12 cells with a membrane-permeable ca lpain inhibitor blocked maitotoxin-induced tan degradation, suggesting the involvement of calpain in calcium-stimulated tau turnover Okadaic acid or the calcineurin inhibitor FK520 partially inhibited maitotoxi n-induced tau dephosphorylation at the Tau-1 epitope, indicating both phosphatase 2A/1 and calcineurin were involved. In addition, FK520, bu t not okadaic acid, blocked the maitotoxin-induced tau degradation, de monstrating that dephosphorylation of specific tan epitopes by was ess ential for calpain-mediated tau degradation. Moreover, maitotoxin effe cts mere likely independent of tau association with microtubules becau se maitotoxin induced tau degradation and dephosphorylation in the pre sence of either nocodazole or taxol. These data provide evidence that calpain is involved in tau turnover in situ and calcineurin plays an i mportant role in modulating tau susceptibility to calpain. J. Neurosci , Res, 53:153-164, 1998. (C) 1998 Wiley-Liss, Inc.