Researchers at Massachusetts Institute for Technology's Picower Institute for Learning and Memory have found a missing protein that may be one of the culprits behind autism and other brain disorders.
They team has uncovered an enzyme called Cdk5, which is the key to missing brain protein called CASK.
CASK plays a major role in the development of synapses, which send and receive signals between neurons and underlie the ability to learn and remember.
Synapses are complex structures consisting of ion channels, receptors and intricate protein complexes that all work together to send and receive signals. Improperly formed synapses can cause mental retardation, and mutations in genes encoding certain synaptic proteins are associated with autism.
In the study, Li-Huei Tsai, Picower Professor of Neuroscience at MIT, found that Cdk5 seems to pave the way for CASK to build synapses between brain cells.
She said while Cdk5's best-known role is to help new neurons form and migrate to their correct positions during brain development, "emerging evidence supports an important role for Cdk5 at the synapse."
To gain a better understanding of how Cdk5 promotes synapse formation, Tsai looked at how Cdk5 interacts with CASK, a key scaffolding protein-is one of the first proteins on the scene of a developing synapse.
Scaffolding proteins such as CASK are like site managers, supporting protein-to-protein interactions to ensure that the resulting architecture is sound. Mutations in the genes responsible for Cdk5 and CASK have been found in mental retardation patients.
"We found that Cdk5 is critical for recruiting CASK to do its job for developing synapses. Without Cdk5, CASK was not in the right place at the right time, and failed to interact with essential presynaptic components. This, in turn, led to problems with calcium influx," Tsai said.
The flow of calcium in and out of neurons affects the nervous system's development and its ability to change in response to experience.
Gene mutations and/or deletions in synaptic cell surface proteins and molecules called neurexins and neuroligins have been associated with autism. The problem with CASK recruitment investigated by the Tsai laboratory creates the same result as these genetic changes.
The study also provides the first molecular explanation of how Cdk5, which also may go awry in neurodegenerative diseases such as Alzheimer's, promotes synapse development.
"There are still a lot of unknowns. Causes for psychiatric disorders are still very unclear, but accumulating evidence strongly suggests that alterations in the synaptogenesis program can lead to these serious diseases," Tsai said.
The new study is published in the Dec. 6 issue of the journal Neuron.