Neuroligin and Autism
The rapid increase in autism spectrum disorder (ASD) diagnoses over the last 15 years is alarming. A number of reasons for the rise have been suggested, some of which have sparked debate that occasionally becomes laden with vitriol. Many people, surprised and frightened by what they see as the unprecedented appearance of a novel disorder, are looking for answers and pointing fingers at parties they feel may be culpable. The etiology of ASD is unknown, and perhaps we will find that some of the impassioned claims made by groups like Generation Rescue are valid. But the idea that the emergence of such a disorder occurred overnight is not completely accurate.
Perhaps the earliest documented case of autism was that of Hugh Blair in 1747 (he was 39 at the time). Over the years other cases were identified, while many were misdiagnosed (frequently as infantile schizophrenia). In the 1940s, Leo Kanner and Hans Asperger developed the foundation for the modern diagnosis of autism by laying out a clearer description of the disorder. Interestingly, Kanner was disturbed by how quickly the rate of diagnosis of new cases of autism rose after his paper was published. This was in the 1950s. Since then, of course, the diagnosis has been refined and subsequently broadened, resulting in the class of ASDs we are familiar with today. In many ways, the history of autism up to this point is not so different from the history of other debilitating disorders like schizophrenia in that it consists of slow acknowledgement of a unique set of symptoms, followed by attempts at classification and an increase in the number of diagnoses due to clearer diagnostic criteria.
How the story of autism plays out is yet to be seen. But as the debate over vaccines and other potential causes continues to smolder, science is plodding along attempting to develop animal models for the study of the disorder. Several genetic mutations have been associated with ASDs. Mutations in genes that encode for proteins involved in the healthy functioning of synapses, called neuroligins and neurexins, have been directly linked to ASD. The result has been that many now classify the disorder as a synaptopathy, or a disease that is primarily caused by synaptic dysfunction. This has also led to the development of neuroligin-3 knockout (KO) mice as a rodent model for ASD.
A study in this month’s issue of The Journal of Biological Chemistry goes a step further in determining exactly how mutations in neuroligin can result in synaptopathies. The group coerced cultured neurons to express neuroligin mutations, which caused the protein to be folded improperly after it was manufactured. Furthermore, the misfolded proteins were not sent from the cell body out to the limits of the neuron. Thus the dendrites had a dearth of the protein, a factor that could be at least partly responsible for the unhealthy synaptic function that occurs when the neuroligin gene is mutated.
Protein misfolding is a culprit in Alzheimer's and Parkinson's disease as well, among others. While this study is an important step toward understanding autism, there are many more questions to be answered about how dependent the disorder may be upon protein misfolding and what other factors may be contributing to its variety of symptoms. And unfortunately attempts at developing treatments for protein misfolding diseases have not yet met with much success. Regardless, this is a positive development in understanding ASDs, a task that remains important not just for their treatment but for quelling the anxiety of a public struggling to understand the troubling incidence of the disorder.
De Jaco, A., Lin, M., Dubi, N., Comoletti, D., Miller, M., Camp, S., Ellisman, M., Butko, M., Tsien, R., & Taylor, P. (2010). Neuroligin Trafficking Deficiencies Arising from Mutations in the / -Hydrolase Fold Protein Family Journal of Biological Chemistry, 285 (37), 28674-28682 DOI:10.1074/jbc.M110.139519