Excerpts from my Dissertation

An international effort to identify "autism-related" genes has demonstrated an association with autism (in some families) of mutations in genes encoding synaptic proteins. It is now generally accepted that mutations affecting structural components of synapses provide a significant risk factor for the development of ASDs. Thus far, the best-studied of these autism-associated proteins are the neuroligins: post-synaptic adhesion/signaling proteins that bind specifically to a set of presynaptic membrane proteins called neurexins.

We investigated the effects of neuroligin disrupting mutations in the nematode Caenorhabditis elegans. Using worms to study the effects of autism-related mutations is not as far-fetched as it might seem. Numerous studies 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. We characterized C. elegans neuroligin, and showed that the protein is quite similar in structure to its mammalian homologs. Worms have a single neuroligin gene (nlg-1), and mutants completely lacking the neuroligin protein have superficially normal growth and behavior, and apparently normal nervous systems. However, nlg-1 mutants have several sensory deficits; for example, they lack the normal (wild-type) response to specific chemicals and they are insensitive to changes in temperature. The mutants also have deficits in the processing of conflicting sensory inputs. The other important results follow from the observation that nlg-1 mutants have increased levels of oxidative stress. Oxidative stress is caused by an excess of free radicals and reactive oxygen species (ROS) that are toxic and can cause damage to cellular components (e.g., proteins, lipids, and DNA). The elevated oxidative stress was demonstrated in two ways. First, nlg-1 mutants are hypersensitive to the toxic effects of paraquat (an herbicide that produces excess free radicals and ROS), implying that the mutants have elevated levels of endogenous free radicals. In addition, the extent of oxidative damage to proteins in nlg-1 mutants was much greater than that found in wild-type animals. Another consequence of the oxidative stress caused by loss of neuroligin in nematodes is that nlg-1 mutants are hypersensitive to the toxic effects of copper and mercury-containing compounds.

Although sensory issues are not part of the official diagnostic criteria for ASDs, problems of sensory hypersensitivity, insensitivity or habituation are commonly reported, as well as difficulties with the processing and/or integration of simultaneous sensory inputs. It is therefore particularly intriguing that nlg-1 mutants have specific sensory deficits, as well as deficits in the processing of conflicting sensory inputs.Another possible similarity between nlg-1 mutants and individuals with ASDs involves oxidative stress. Oxidative stress is caused by an excess of free radicals and ROS, and there are many examples of mutations in detoxifying enzymes or mitochondrial proteins that result in oxidative stress. However, the elevated oxidative stress present in nlg-1 mutants is a completely unexpected phenotype for a synaptic protein mutant.