Biology Reference
In-Depth Information
With activation of GSK-3, both presynaptic release of glutamate and expression of
postsynaptic proteins decreased, and LTP-associated synaptic impairments were observed
morphologically. These lesions were partially but significantly restored with a concomitant
inhibition of the GSK-3 upregulation [Zhu
et al.,
2007]. These results reveal that GSK-3
activation impairs synaptic plasticity both functionally and structurally, which may underlie
the GSK-3-involved deficits in learning and memory.
The PI3K/Akt signaling pathway is of central importance for neuronal physiology. In
addition to its role in neuronal cell survival [Brunet
et al.,
2001] this pathway has been
implicated in dendritic morphogenesis [Jaworski
et al.,
2005], establishment of neuronal
polarity [Jiang
et al.,
2005], synaptic potentiation [Opazo
et al.,
2003; Wang
et al.,
2003] and
memory formation [Lin
et al.,
2001; Mizuno
et al.,
2003]. In addition, PI3K/Akt signaling
regulates translation by activating mTOR (mammalian target of rapamycin [Ruggero and
Sonenberg, 2005] and suppresses the activity of GSK-3 [Cross
et al.,
1995]. Presenilin-1
(PS1) is a ubiquitously expressed transmembrane protein that plays critical roles in
development [Shen
et al.,
1997; Wong
et al.,
1997] and in FAD [Sherrington
et al.,
1995].
Recent studies in fibroblasts implicate PS1 in the regulation of the PI3K/Akt signaling
pathway [Baki
et al.,
2004; Uemura
et al.,
2007]. In this context, newly published data [Baki
et al.,
2008] propose that wild-type PS1 prevents neuronal degeneration by promoting
PI3K/Akt signaling, while PS1 FAD mutations increase GSK-3 activity and promote
neuronal apoptosis by inhibiting the function of PS1 in this pathway. These observations
suggest that stimulation of PI3K/Akt signaling may be beneficial to FAD patients.
Cyclin-dependent kinase 5
Cyclin-dependent kinase 5 (Cdk5) belongs to the family of serine/threonine cyclin-
dependent kinases. Despite its high degree of homology to other cyclin-dependent kinases,
Cdk5 stands alone in this family by virtue of not being activated by cyclins [Liu and Kipreos,
2000]. Cdk5 plays an important role in a range of physiological and pathological processes.
This multifunctionality is best characterized in neurons and includes involvement in nervous
system development, dopaminergic function and neurodegeneration, and is reviewed
elsewhere [Dhavan and Tsai, 2001; Shelton and Johnson, 2004]. Cdk5 has been reported to
affect pre-synaptic molecular mechanisms, including modulation of voltage-dependent
calcium channels and vesicle cycling. Post-synaptically, Cdk5 plays a role in the clustering of
proteins, modulation of ion channels and intracellular signaling by regulating PKA and the
MAPK pathway, as well as protein phosphatases. Extra-synaptic processes affected by Cdk5
include cell adhesion, transcription and protein translation. In addition, Cdk5 has been
implicated in the direct phosphorylation of numerous substrates relevant to synaptic plasticity
[reviewed in Angelo
et al.,
2006]. Collapsin response mediator protein (CRMP) is a signaling
molecule of semaphorin3A (Sema3A) [Goshima
et al.,
1995], one member of the semaphorin
family of repellent axonal guidance cues [Raper, 2000]. Sema3A functions not only as a
chemorepulsive cue but also in endocytosis, facilitation of axonal transport, and spine
development [Nakamura
et al.,
2000; Morita
et al.,
2006] through the Fyn-Cdk5 cascade
[Morita
et al.,
2006]. How Sema3A regulates the cytoskeleton has remained unclear, although
a new report [Yamashita
et al.,
2007] suggests that regulation of spine development by
Sema3A occurs through Cdk5 phosphorylation of CRMP1, one of the five CRMP family
members [Wang and Strittmatter, 1996].
