bp(GO:"anterograde axonal protein transport")
APP undergoes rapid anterograde transport in neurons PubMed:21214928
As observed with 2–18 tau aggregates (LaPointe et al., 2009), monomeric 2–18 6D tau showed no effect on FAT (Fig. 4 A, D), demonstrating that PAD is necessary for 6D tau- mediated inhibition of anterograde FAT. PubMed:21734277
The PAD peptide selectively in- hibited anterograde FAT (Fig. 4 B, D), but not retrograde FAT (Fig. 4B,E). PubMed:21734277
Collectively, these data indicate that PAD is both necessary and sufficient to inhibit an- terograde FAT by activating the PP1–GSK3 cascade. PubMed:21734277
perfusion of full-length WT tau monomers (2 M) (Fig. 1 A) had no effect on FAT in squid axoplasm (Fig. 2 A), while 6D and 6P tau monomers (2 M) significantly inhibited anterograde FAT when compared with WT tau monomer (Fig. 2 B, C) or buf- fer controls (data not shown). PubMed:21734277
Together, these data demonstrate that, as posited for aggregated tau (LaPointe et al., 2009), short N-terminal isoforms of tau inhibit anterograde FAT by a mech- anism involving activation of PP1 and GSK3 that is independent of microtubule binding. PubMed:21734277
perfusion of full-length WT tau monomers (2 M) (Fig. 1 A) had no effect on FAT in squid axoplasm (Fig. 2 A), while 6D and 6P tau monomers (2 M) significantly inhibited anterograde FAT when compared with WT tau monomer (Fig. 2 B, C) or buf- fer controls (data not shown). PubMed:21734277
Soluble AT8 tau monomers inhibited anterograde FAT (Fig. 6 A, C), while retrograde trans- port was unaffected (Fig. 6 A, D). These data indicate that phos- phorylation of tau at the AT8 epitope, which is associated with hyperphosphorylation of tau in AD and other tauopathies, renders soluble monomeric tau capable of inhibiting antero- grade FAT. PubMed:21734277
Consistent with our model, 144 –273 tau monomers significantly inhibited antero- grade FAT (Fig. 6 B, C), while retrograde FAT remained unaf- fected (Fig. 6 B, D).Together, these data indicate that disease- associated modifications and mutations in tau that increase exposure of PAD promote activation of the PP1–GSK3 pathway and inhibition of anterograde FAT. PubMed:21734277
Together, these data demonstrate that, as posited for aggregated tau (LaPointe et al., 2009), short N-terminal isoforms of tau inhibit anterograde FAT by a mech- anism involving activation of PP1 and GSK3 that is independent of microtubule binding. PubMed:21734277
Together, these data demonstrate that, as posited for aggregated tau (LaPointe et al., 2009), short N-terminal isoforms of tau inhibit anterograde FAT by a mech- anism involving activation of PP1 and GSK3 that is independent of microtubule binding. PubMed:21734277
Additionally, studies have discovered that aggregated tau inhibits fast axonal transport in the anterograde direction at all physiological tau levels, whereas tau monomers have had no effect in either direction (LaPointe et al., 2009; Morfini et al., 2009) PubMed:28420982
As previously reported, perfusion of hT40 monomer had no effect on the rate of anterograde FAT in the squid axoplasm (Fig. 5A), whereas perfusion of hT40 aggregates significantly inhibited anterograde FAT as compared to hT40 monomer (Fig. 5B; Fig. 6A; p = 0.003) (LaPointe et al., 2009b). Neither hT40 monomers nor hT40 aggregates altered the rate of retrograde FAT (Fig. 5A, B; Fig. 6B). PubMed:27373205
As previously reported, perfusion of hT40 monomer had no effect on the rate of anterograde FAT in the squid axoplasm (Fig. 5A), whereas perfusion of hT40 aggregates significantly inhibited anterograde FAT as compared to hT40 monomer (Fig. 5B; Fig. 6A; p = 0.003) (LaPointe et al., 2009b). Neither hT40 monomers nor hT40 aggregates altered the rate of retrograde FAT (Fig. 5A, B; Fig. 6B). PubMed:27373205
In contrast to hT40 monomer, perfusion of S422E monomer selectively inhibited anterograde transport (Fig. 5C; Fig. 6A; p = 0.028), but not retrograde FAT. Surprisingly, aggregated S422E significantly inhibited both anterograde and retrograde FAT rates (Fig. 5D; Fig. 6A, B) compared to S422E monomer (anterograde, p = 0.012; retrograde, p = 0.002) and hT40 aggregates (retrograde only, p = 0.019). PubMed:27373205
In contrast to hT40 monomer, perfusion of S422E monomer selectively inhibited anterograde transport (Fig. 5C; Fig. 6A; p = 0.028), but not retrograde FAT. Surprisingly, aggregated S422E significantly inhibited both anterograde and retrograde FAT rates (Fig. 5D; Fig. 6A, B) compared to S422E monomer (anterograde, p = 0.012; retrograde, p = 0.002) and hT40 aggregates (retrograde only, p = 0.019). PubMed:27373205
Using a squid axoplasm assay, we have demonstrated that aggregated tau inhibits anterograde FAT (fast axonal transport), whereas monomeric tau has no effect PubMed:22817713
We discovered that aggregated tau inhibits FAT only in the anterograde direction at physiological tau levels, whereas tau monomers had no effect on FAT in either direction, even at concentrations of tau >10-fold higher than PubMed:22817713
However, when tau aggregates, this conformation is altered, exposing PAD and allowing activation of the PP1/GSK3 signalling pathway facilitating FAT inhibition [21] PubMed:22817713
We illustrate that Hsp70 preferentially binds to tau oligomers over filaments and prevents anterograde FAT inhibition observed with a mixture of both forms of aggregated tau PubMed:22817713
However, our data indicate that Hsp70 preferentially binds to oligomeric as opposed to fibrillar tau aggregates and prevents anterograde FAT inhibition [31] PubMed:22817713
Furthermore, when Hsp70 was pre-incubated with the PAD peptide and introduced to the squid axoplasm, inhibition of FAT was still observed [31] PubMed:22817713
Deletion analyses demonstrate that FAT inhibition requires a small stretch of amino acids (residues 2–18) located within the N-terminus that we have termed the PAD (phosphataseactivation domain) [21] PubMed:22817713
Further investigation illustrated that this inhibition occurs via activation of a signalling cascade involving PP1 (protein phosphatase 1) and GSK3 (glycogen synthase kinase 3) [24] PubMed:22817713
Further investigation illustrated that this inhibition occurs via activation of a signalling cascade involving PP1 (protein phosphatase 1) and GSK3 (glycogen synthase kinase 3) [24] PubMed:22817713
Tau serves an important function by enabling microtubules to connect with cytoskeletal components and facilitates anterograde and retrograde axonal transport of vesicles and organelles [39]. PubMed:29758300
APP undergoes rapid anterograde transport in neurons PubMed:21214928
As observed with 2–18 tau aggregates (LaPointe et al., 2009), monomeric 2–18 6D tau showed no effect on FAT (Fig. 4 A, D), demonstrating that PAD is necessary for 6D tau- mediated inhibition of anterograde FAT. PubMed:21734277
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If you find BEL Commons useful in your work, please consider citing: Hoyt, C. T., Domingo-Fernández, D., & Hofmann-Apitius, M. (2018). BEL Commons: an environment for exploration and analysis of networks encoded in Biological Expression Language. Database, 2018(3), 1–11.