Abstract:

Recent studies suggest that cell cycle pathways may contain therapeutic targets important for neurotrauma. An example of this is the finding that the vertebrate cell cycle exploits proteolysis pathways yet these activities persist in fully differentiated cells that have exited the cell cycle such as neurons. We have known for some time that a ubiquitin ligase, the Anaphase-Promoting Complex (APC/C) required for progression through the M and G1 phases of the cell cycle, is also active in fully differentiated neurons that are no longer dividing. Several studies demonstrated roles for APC/C in restraining neurite outgrowth in fully differentiated neurons. Depleting the APC/C activator Cdh1 increased neurite outgrowth in cerebellar granule cells. Similarly, overexpression of nondegradable APC/C substrates such as SnoN and Id2 promoted neurite outgrowth in cerebellar granule cells. Interestingly, nondegradable Id2 overexpression increased neurite outgrowth in a regeneration model, suggesting that modulating protein levels by affecting their degradation rates may be therapeutically attractive in preclinical models of neurotrauma. In addition to in vitro studies with CK1δ it will be important to determine whether CK1δ inhibition reduces neurite outgrowth in vivo in naïve animals but also in models of spinal cord injury. Given the reported role for CK1δ in neurite outgrowth in vitro the prediction is that CK1δ inhibition should reduce neurite outgrowth. However, after spinal cord injury neurite outgrowth is also affected by inflammation. Studies have shown that inhibition of inflammation in astrocytes reduces inflammation and increases neurite outgrowth after SCI. Thus, a possible role for CK1δ in promoting inflammation after SCI may suggest that CK1δ inhibition may be therapeutically attractive. Consistent with this notion is the finding that CK1δ inhibition reduces neuropathic pain after SCI, possibly via reducing inflammation. Future studies will delineate the role of CK1δ in promoting inflammation and neurite outgrowth after SCI. Furthermore, the contribution of APC/C dependent degradation should be analyzed to determine whether it is feasible to simultaneously stimulate APC/C-dependent degradation of CK1δ in inflammatory cells while inhibiting the APC/C-CK1δ interaction in neurons.