11 December 2007. In the December 6 Neuron, Li-Huei Tsai and colleagues at MIT report that the kinase Cdk5 controls the distribution of the synapse scaffold protein CASK. The finding strengthens the case that Cdk5, perhaps best known for its role in developmental regulation, also acts in synaptogenesis.
Alzheimer disease researchers are quite familiar with Cdk5, as it promotes both amyloid production (see ARF related news story) and tau phosphorylation (see ARF related news story), two major features of the disease. It has also been linked to degradation of synapses, though not in a kinase-dependent manner (see ARF related news story). The presently reported, new role of Cdk5 in synaptogenesis may pique interest among AD researchers as well, given that loss of synapses may be the best pathological correlate of cognitive decline (see, e.g., DeKosky et al., 1990).
There has been increasing evidence that Cdk5 somehow helps regulate synapses. The kinase phosphorylates several synaptic proteins, including PSD95, and Tsai and colleagues previously demonstrated that transient expression of the Cdk5 activator p25 in mice boosts synapse numbers and improves learning and memory (see ARF related news story). This current paper hints that those cognitive improvements may be related to CASK.
CASK is believed to be a synaptic scaffold protein that supports the architecture necessary for efficient synaptic function. It is recruited to synapses by synaptic proteins SynCam and neurexins/neuroligins. First author Benjamin Samuels and colleagues report that when Cdk5 phosphorylates CASK, this stimulates the association of CASK with membranes, particularly synaptosomes. Expressing a mutant form of CASK that cannot be phosphorylated in cells compromises the cells’ calcium influx.
“CASK represents a novel substrate of Cdk5 that provides a potential mechanism to explain how Cdk5 can drive formation of new synapses,” write the authors. The finding could have implications for studying neurologic diseases. As the authors point out, mutations in neuroligins, which help recruit CASK, have been linked to autism, and CASK has also been linked to parkin, which is mutated in some familial forms of Parkinson disease (see Fallon et al., 2002).—Tom Fagan.
Samuels BA, Hsueh Y-P, Shu T, Liang H, Tseng H-C, Hong C-J, Su SC, Volker J, Neve RL, Yue DT, Tsai L-H. Cdk5 promotes synaptogenesis by regulating the subcellular distribution of the MAGUK family member CASK. Neuron. 2007 Dec 6;56:823-837. Abstract