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Genetic Models of Disease Research Program

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Research points to possible links between autism and sensitivity to environmental toxins

For OMRF autism researcher, work is personal

James B. Rand, Ph.D. Member and Program Chair, Genetic Models of Disease Research Program H.A. and Mary K. Chapman Chair in Medical Research Adjunct Professor, Department of Cell Biology, University of Oklahoma Health   Sciences Center Adjunct Professor, Oklahoma Center for Neuroscience

Research Interests
For more than 20 years, we have been using the soil nematode Caenorhabditis elegans to identify and characterize synaptic proteins, and to determine how mutational loss of these proteins leads to altered behaviors. The simple, 302-cell nervous system of C. elegans is well suited for such studies because we can apply powerful tools of genetics, cell biology, and molecular biology to analyze the structure and function of the nervous system. In fact, numerous studies (including many from our laboratory) have shown that C. elegans neuronal proteins are structural and functional homologs of the corresponding mammalian proteins, and it is now well established that C. elegans provides a powerful model for analyzing synapse structure, function, and development.

In the past, we have studied genes and proteins involved in the transport of specific neurotransmitters or groups of neurotransmitters, as well as genes and proteins involved in the general release mechanism of all neurotransmitters. Recently, we have begun to study molecules involved in synapse formation, using C. elegans mutants with aberrant synapse structural components as a model for the study of autism and autism spectrum disorders (ASDs). These are developmental disorders associated with atypical socialization, communication, and behavior, and are often accompanied by sensory deficits and abnormalities in sensory processing, cognitive function, and learning. A recent study released by the Centers for Disease Control and Prevention (CDC) reported that the prevalence of ASDs is increasing, and they now affect approximately one in every 110 children.

Although environmental factors clearly play a role in the etiology and severity of ASDs, family studies have shown that ASDs also have a strong hereditary (i.e., genetic) basis, apparently involving a large number of genes. One of the most striking results emerging from the intensive international effort to identify such "autism-related" genes has been the demonstration of an association with autism (in some families) of mutations in genes encoding synaptic proteins. Thus far, the best-studied of these autism-associated genes and proteins are the genes encoding neuroligins. Neuroligins are adhesion/signaling proteins present on post-synaptic cell membranes, and they bind specifically to a set of presynaptic membrane proteins called neurexins. There are 4 neuroligin-encoding genes in humans, and mutations disrupting NLGN3 and NLGN4 are associated with ASDs. 

Taking advantage of our experience studying synapse development and function, we have begun to investigate the properties of neuroligin in C. elegans and the cellular and behavioral consequences of neuroligin-deficient mutations. C. elegans has a single neuroligin-encoding gene (nlg-1), and we have shown that the protein it encodes is quite similar to mammalian neuroligins. Null nlg-1 mutants (lacking all protein function) are viable and superficially wild-type in their appearance, development and behavior. In addition, the nervous system of nlg-1 mutants is grossly normal. Upon closer inspection, however, nlg-1 mutants display subtle sensory deficits, including a lack of sensitivity to some chemicals, insensitivity to changes in temperature, and altered processing of simultaneous sensory inputs. Such sensory abnormalities mirror many anecdotal reports from families as well as some research on children and adolescents with ASDs.

During the course of our studies on neuroligin mutants in C. elegans, we discovered that, in addition to sensory deficits, these mutants have increased levels of oxidative stress. This was unexpected, because mutations in synaptic proteins had not previously been associated with oxidative stress. It was also noteworthy because of studies documenting increased oxidative stress in individuals with autism. Although we do not yet understand the exact mechanism by which the loss of neuroligin leads to oxidative stress, it is striking that a mutation which, in humans, is associated with autism should produce a similar oxidative stress phenotype in C. elegans. What is still needed, however, is a detailed understanding of the mechanisms by which perturbations of synaptic proteins lead to specific metabolic deficits as well as to alterations of cells and circuits within a functioning nervous system. 

Autism and Oxidative Stress: Correlations, Models, and Causality. Although a number of studies have been published demonstrating elevated markers of oxidative stress in individuals with ASDs, the nature of the possible relationship between autism and oxidative stress has never been clear. At best, such studies provide no more than a correlation between oxidative stress and ASDs, yet a model often proposed is that oxidative stress (perhaps resulting from environmental toxins) somehow causes or contributes to the etiology of ASDs. Our studies in C. elegans demonstrate that loss of the synaptic protein neuroligin is not merely correlated with oxidative stress, but it actually causes the oxidative stress. Therefore, if oxidative stress is a consequence of aberrant synaptic proteins in nematode neurons, then it seems plausible to expect that aberrations of synaptic proteins in human neurons might have similar consequences. This raises the intriguing possibility that in humans, specific types of neuronal disruption (such as mutations affecting synaptic adhesion proteins) might be the cause, rather than the result, of oxidative stress.

Information about diagnosis and treatment of ASDs and useful resources may be found at websites of the National Institutes of Health (NIH) and the Centers for Disease Control and Prevention (CDC).

Joined OMRF Scientific Staff in 1989.

Mailing Address
Genetic Models of Disease Research Program, MS 48
Oklahoma Medical Research Foundation
825 N.E. 13th Street
Oklahoma City, Oklahoma 73104

Contact Information
Phone: (405) 271-7681
Fax: (405) 271-7312
E-mail: James-Rand@omrf.org