Biology Reference
In-Depth Information
stimuli (
Suzuki & Koike, 2007
). Interestingly, Cdk5 phosphorylates SIRT2
at Ser331, a conserved site among several Sirtuin family members, and in-
hibits its deacetylase activity (
Pandithage et al., 2008
). In light of the critical
role of SIRT2 in regulating the microtubule stability, it is tempting to spec-
ulate that Cdk5-mediated inhibition of SIRT2 is involved in axon regener-
ation. Taken together, these observations reveal a novel mechanism
whereby Cdk5 may support axon growth and regeneration by inhibiting
SIRT2 and increasing tubulin acetylation and microtubule stabilization.
2.3.3 Modulating axonal transport
Under developmental and regenerative conditions, the vast majority of the
axonal building components, such as membranes and proteins, are synthe-
sized in the neuronal cell body and delivered along the axon shafts toward
the growing axon tips through axonal transport. Defects in axonal transport
lead to degeneration of the axons underlying various pathological conditions
such as injury and motor neuron diseases (
El-Kadi, Soura, & Hafezparast,
2007
). Axonal transport can be divided into anterograde transport, which
refers to the movement of materials and organelles from the soma to the
axonal compartment, and retrograde transport, which is essential to
transduce extracellular stimuli and injury signals to the soma. Moreover,
transportation of axonal materials destined for degradation to the soma,
where they are broken down by proteasomes or lysosomes, also depends
on retrograde transport. Axonal transport not only requires the microtubules
serving as cytoskeletal scaffold, but also relies on the motor proteins (kinesin
and dynein), acting as the mechanical force to move cargoes anterogradely
or retrogradely (
Goldstein & Yang, 2000
).
Interestingly, Cdk5 regulates axonal transport by modulating the func-
tions of kinesin and dynein. On one hand, Cdk5 is essential for kinesin-
driven motility through inhibition of GSK-3
b
. The critical role of Cdk5
in the regulation of kinesin function is demonstrated by the observation that
pharmacological blockade of Cdk5 activity inhibits kinesin-mediated anter-
ograde vesicle transport. In particular, Cdk5-mediated suppression of GSK-
3
b
is required to limit GSK-3
b
activity to a relatively low level, and thus
prevents GSK-3
b
-mediated cargo release from kinesin and safeguards axonal
transport (
Morfini et al., 2004
). On the other hand, Cdk5 has also been
suggested to modulate dynein function through phosphorylation of a
dynein-interacting protein, NUDEL (
Niethammer et al., 2000; Sasaki
et al., 2000
). Specifically, Cdk5-mediated phosphorylation of NUDEL
occurs at multiple residues
located in the dynein binding region,
