Biology Reference
In-Depth Information
be of interest to examine whether Cdk5 plays a role in axon regeneration
in the presence of exogenous stimulation after CNS injury, and also to
investigate the interaction between different Cdk5-mediated pathways.
Taken together, it is clear from a myriad of studies that Cdk5 potentially
regulates the developmental and regenerative axon growth through
phosphorylation-mediated regulation of multiple cellular processes. Specifi-
cally, Cdk5 modulates downstream signaling of extracellular signals, including
neurotrophins and axon guidance molecules. In addition, Cdk5 enables effi-
cient cytoskeletal reorganization through various Rho GTPases and MAPs.
Moreover, Cdk5 regulates protein synthesis and gene transcription by phos-
phorylating various translational and transcriptional regulators. Therefore,
Cdk5 appears to be a plastic kinase that maintains the neural plasticity for axon
growth during the development and axon repair after injury (
Fig. 5.1
).
Although Cdk5 is extensively involved in regulating multiple cellular
processes that are important for axon regeneration, it is not applicable to
hyperactivate Cdk5 activity to promote axon regeneration, since deregula-
tion of Cdk5 in both directions is associated with various neurodegenerative
diseases (
Cheung & Ip, 2012
). Indeed, hyperphosphorylation of Tau by
Cdk5 is a major hallmark of Alzheimer's disease (
Hardy, 2006
). Further,
maintaining a proper level of Cdk5 activity appears to be critical for neuronal
survival, as Cdk5 supports neuronal survival through phosphorylation of
antiapoptotic Bcl-2 (
Cheung, Gong, & Ip, 2008
), whereas hyperactivation
of Cdk5 by p25 leads to neuronal cell death (
Patrick et al., 1999
).
Instead of directly modulating Cdk5 activity, targeting cellular processes
downstream of Cdk5, including cytoskeleton dynamics and protein synthe-
sis, will be more applicable and generate better specificity. For example, to
promote microtubule stabilization, Axin and SIRT2 are promising molec-
ular targets. Enhancing the interaction between Axin and GSK3
b
will lead to GSK3
b
inhibition, which favors axon regrowth by stabilizing
microtubule cytoskeleton and facilitating axonal transport. In addition,
inhibition of SIRT2 will produce therapeutic benefit on promoting
axon regeneration. Furthermore, to safeguard protein expression for
axon regeneration, APC/Cdh1-mediated protein degradation pathway
can be manipulated through blockade of the interaction between Cdh1
and APC by competing peptide or small molecule.
Aside from modulating a single signaling molecule, recent studies
demonstrated that combinatorial manipulation of extrinsic and intrinsic
mechanisms (
Alilain, Horn, Hu, Dick, & Silver, 2011; Kadoya et al., 2009
)
and coactivation of multiple intracellular pathways (
Sun et al., 2011
)
