In the latest edition of the journal Neuron, researchers from the Massachusetts Institute of Technology’s Picower Institute for Learning and Memory and the Howard Hughes Medical Institute – Department of Brain and Cognitive Sciences, have reported that Cdk5, an enzyme crucial for the activity of the brain protein CASK (calcium/calmodulin-dependent serine protein kinase), plays a major role in synaptogenesis, and that the absence of the CASK protein may be one of the causes of autism and other brain disorders.
The team suggested that cdk5 promotes synapse formation by interacting with synapse-inducing proteins such as CASK. They concluded that Cdk5-mediated phosphorylation regulates the distribution of CASK to the neuronal membranes, vital for the interaction between the presynaptic, neural membrane components -SynCAM and Neurexins/Neuroligins – for synapse formation. Absence of Cdk5-dependent phosphorylation alters calcium influx, necessary for nervous system function and neuron plasticity. The presence of mutated versions of Cdk5 and CASK genes in mentally retarded patients adds credence to these findings.
Cdk5, a proline-directed serine/threonine kinase, regulates neuronal migration, neuronal survival, and synaptic functions. In another recent study, Cheung et al (Biotechnology Journal, 2007) further demonstrated the potential role of Cdk5 in dendrite and synapse development. Cdk5 is also known to regulate the function of various extracellular factors involved in neurite extension, synapse and even spine maturation.
Autism, a complex behavioral disability, affecting the pediatric population, is grouped under a broad spectrum of developmental disorders known as autism spectrum disorders (ASDs). Other ASDs include Asperger syndrome, Rett syndrome, childhood disintegrative disorder, and pervasive developmental disorder not otherwise specified (PDD-NOS). According to a recent statistical release from the CDC’s Atlanta based program, approximately 3-6 of every 1000 children (3-10 years) in the U.S are affected with autism spectrum disorders, and the risk is 3-4 times higher in males than females.
Autism is characterized by impaired social interaction, problems with verbal and nonverbal communication, unusual and repetitive behaviors, and severely limited activities and interests. A combination of genetic, neuropathologic, psychopathologic, and various environmental factors such as toxic exposures, teratogens, perinatal insults, prenatal viral infections (rubella and cytomegalovirus) have been implicated in the development of autism. Currently, there is no specific treatment for autism spectrum disorders; however various behavioral intervention programs and therapies are designed to alleviate specific symptoms to bring about substantial improvement in autistic individuals. Antidepressant medications are prescribed to manage symptoms of anxiety, depression, or obsessive-compulsive disorder.
Targeted research and unravelling the molecular basis of autism could pave the way for developing novel treatment strategies for the autism spectrum disorders.
References
1. Samuels BA, Hsueh YP, Shu T. Cdk5 promotes synaptogenesis by regulating the subcellular distribution of the MAGUK family member CASK. Neuron. 2007 December; 56:823-837.
2. Cheung ZH, Ip NY.The roles of cyclin-dependent kinase 5 in dendrite and synapse development. Biotechnology Journal. 2007 August; 2(8):949- 57.
3. Santangelo SL, Tsatsanis K. What is known about autism: genes, brain and behavior. American Journal of Pharmacogenomics. 2005; 5(2): 71- 92.
