EBD Blog

Professor Li-Huei Tsai of the Massachusetts Institute of Technology and colleagues there and elsewhere have identified the role played by an enzyme that alters proteins critical for building neural connections during learning. Gene mutations or deletions that affect proteins used in synapses have been associated with autism, and the problem that Professor Tsai and her colleagues studied produces the same result as the genetic changes.

A missing brain protein may be one of the culprits behind autism and other brain disorders, according to researchers at MIT’s Picower Institute for Learning and Memory.

The protein, called CASK, helps in the development of synapses, which neurons use to communicate with one another and which underlie our ability to learn and remember. Improperly formed synapses could lead to mental retardation, and mutations in genes encoding certain synaptic proteins are associated with autism.

In work published in the Dec. 6 issue of Neuron, Li-Huei Tsai, Picower Professor of Neuroscience at MIT, reported that she has uncovered an enzyme that is key to the activity of CASK.

Here is the abstract from the journal:

Cdk5 Promotes Synaptogenesis by Regulating the Subcellular Distribution of the MAGUK Family Member CASK

Benjamin Adam Samuels1, 2, 3, Yi-Ping Hsueh5, Tianzhi Shu2, Haoya Liang6, Huang-Chun Tseng2, Chen-Jei Hong5, Susan C. Su2, Janet Volker4, Rachael L. Neve7, David T. Yue6 and Li-Huei Tsai1, 2,

1Howard Hughes Medical Institute, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
2Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
3Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA
4Department of Pathology, Harvard Medical School, Boston, MA 02115, USA
5Institute of Molecular Biology, Academia Sinica, Taipei 115, Taiwan
6Department of Biomedical Engineering and Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
7Department of Psychiatry, McLean Hospital, Belmont, MA 02178, USA
Received 22 January 2007; revised 8 June 2007; accepted 26 September 2007. Published: December 5, 2007. Available online 5 December 2007.

Summary

Synaptogenesis is a highly regulated process that underlies formation of neural circuitry. Considerable work has demonstrated the capability of some adhesion molecules, such as SynCAM and Neurexins/Neuroligins, to induce synapse formation in vitro. Furthermore, Cdk5 gain of function results in an increased number of synapses in vivo. To gain a better understanding of how Cdk5 might promote synaptogenesis, we investigated potential crosstalk between Cdk5 and the cascade of events mediated by synapse-inducing proteins. One protein recruited to developing terminals by SynCAM and Neurexins/Neuroligins is the MAGUK family member CASK. We found that Cdk5 phosphorylates and regulates CASK distribution to membranes. In the absence of Cdk5-dependent phosphorylation, CASK is not recruited to developing synapses and thus fails to interact with essential presynaptic components. Functional consequences include alterations in calcium influx. Mechanistically, Cdk5 regulates the interaction between CASK and liprin-α. These results provide a molecular explanation of how Cdk5 can promote synaptogenesis.

Links to the MIT press release and to the abstract from Neuron (where, if you or your institution subscribes to the journal, you can probably get the full text of the study).