Pinpointing the specific molecular defects that cause autism is a key approach to developing appropriate treatments for the disorder. One way to uncover a disrupted molecular pathway is by identifying single-gene mutations that are associated with the disease, as has been done in Alzheimer’s and Parkinson’s. Although these mutations occur in only five to ten percent of individuals with the latter two disorders, studies have found that the same pathways are also at work in the more common, and more genetically complex disease forms.

Troy Littleton and his colleagues at the Massachusetts Institute of Technology are applying the same approach to autism. The researchers are examining one pathway in particular — the development of junctions between nerve cells, known as synapses — which is likely to be disrupted by at least one single-gene mutation carried by people with autism. The Littleton laboratory has shown that regulation of endosomes — enclosed ‘sacs’ that transport proteins within the cell — is crucial to synaptic development and flexibility. Other researchers recently discovered that a protein found on these endosomes, NHE9, is mutated in some people with autism.

Littleton’s group is using the well-established Drosophila melanogaster fruit fly model to examine whether— and if so, how — mutations in the NHE9 gene disrupt endosomal function and thus prevent adequate transport of growth-promoting factors to synapses during neuronal development. Among other functions, NHE9 regulates the pH level within endosomes; a pH imbalance caused by NHE9 mutations could thus lead to altered degradation of the proteins being transported. The lab has found that NHE9 is present on both early and recycling populations of endosomes, but is absent from the more acidic lysosomal compartment, where protein degradation occurs. Deletion of the NHE9 protein results in viable flies, but the animals show defects in synaptic growth, suggesting a role in nervous system maturation.

By defining the role of NHE9 in synaptic development — and how the process is derailed by mutations in the gene — Littleton and colleagues hope to shed light on one of the malfunctioning molecular cascades that contribute to the pathology of autism.