Fig. 6.

Increased cytoplasmic crowding disrupts circadian rhythms. (A) Circadian rhythms are lengthened in a tauopathy model, Tg4510. Period was significantly longer in Tg4510 mice compared with littermate nontransgenic mice (n = 8 each; P < 0.01, two-tailed t test). Data are mean ± SEM. Tg mice showed increased activity levels (n = 8 each; P < 0.01, two-tailed t test), suggesting that lengthened rhythms are not due to degenerative neuronal activity at this stage. Data are mean ± SEM. Increased tau tangles were confirmed by immunoblotting for pSer396. (B) Cooperative phosphorylation of PER is driven by transacting phosphorylation of CK1δ/ε. PER multimerization, at least dimerization, is required for hyperphosphorylation of PER. PER molecules are trafficked toward the nucleus while being hypophosphorylated (brown) throughout the cytoplasm. PER multimerization is highly favorable only in the perinucleus, where they are hyperphosphorylated (blue) for nuclear entry by transacting CK1δ/ε.