The present results are consistent with this, since we first observed that the acute administration of (PhTe)2 in rats elicited hyperphosphorylation of GFAP, vimentin and NF subunits, evidencing a response of the cytoskeleton of astrocytes and neurons, Galunisertib research buy to the action of the neurotoxicant. Accordingly, NFLSer55 appeared to be a specific amino-terminal phosphorylation site targeted by (PhTe)2, PKA being
the most prominent protein kinase mediating this effect. It is important to note that PKA (Ser-55), PKC (Ser-51) and PKCaMII (Ser-57) phosphorylation sites are relevant for filament assembly. Furthermore, the phosphate present in Ser55 of NF-L is turned over rapidly following NF-L synthesis in neurons (Sihag and Nixon, Selleck Decitabine 1991), suggesting a possible role in the blockade of NF assembly before their transport into neurites. Like NF-L, PKA-mediated phosphorylation of the head
domain of GFAP inhibits filament assembly or induces disassembly (Hisanaga et al., 1994). Therefore, our results showing NF-LSer55 hyperphosphorylation suggest a key role of (PhTe)2 on IF dynamics preventing filament assembly and disassembling preexisting filaments. It is known that carboxyl-terminal phosphorylation of NF-H progressively restricts the association of NFs with kinesin, the axonal anterograde motor protein, and stimulates its interaction with dynein, the axonal retrograde motor protein (Motil Methocarbamol et al., 2006). This event could represent one of the mechanisms by
which carboxyl-terminal phosphorylation would slow NF axonal transport. Consistent with this, MAPK phosphorylates NF-M and NF-H tail domains at specific carboxyl-terminal located KSP repeats (Veeranna et al., 1998) and alters the association of NF with motor proteins (Yabe et al., 2000). It is feasible that extensively phosphorylated KSP repeats on NF-M and NF-H as well as MAPK (Erk, JNK and phospho38MAPK) activation we found in the striatum of (PhTe)2-treated rats could interfere with NF axonal transport and contribute, at least in part, to the neuronal damage provoked by the neurotoxin. Taking into account the present findings, we are tempted to speculate that disruption of cytoskeletal homeostasis in the striatum of injected rats, could be related with the neurodegeneration provoked by the (PhTe)2. This hypothesis is supported by the evidence that p38MAPK and JNK signaling pathways are supposed to act synergistically upstream of mechanisms leading to apoptotic neuronal death in different models of neurodegeneration (Muscella et al., 2011). To better understand the molecular mechanisms underlying neuronal loss in acutely (PhTe)2 injected rats, we assayed the caspase 3 activity and we found that this caspase is activated 6 days after exposure.
No related posts.