A major obstacle impeding the development of effective treatments for autism is the complexity of factors, such as genetic mutations, epigenetics and environmental influences that contribute to the disorder. However, research over the past few years suggests that ‘hot spots’ of cellular dysfunction are shared across autism spectrum disorders of different etiologies.

One of these is the phosphoinositide 3-kinase/mammalian target of rapamycin (PI3K/mTOR) signaling complex, which regulates protein synthesis. Emerging evidence shows that defects in PI3K/mTOR signaling and dysregulated protein synthesis play a significant role in many types of autism. Christina Gross, Gary Bassell and their colleagues at Emory University in Atlanta, Georgia, examined how these shared pathological mechanisms may be used as biomarkers or therapeutic targets in autism.

The researchers performed an unbiased screen of cell lines from the Simons Simplex Collection (SSC), in which they compared PI3K/mTOR signaling in 39 cell lines from people with autism spectrum disorders with signaling in cell lines from their unaffected siblings. They also analyzed whether defects in PI3K signaling can be detected in blood lymphocytes from people with the inherited autism spectrum disorder fragile X syndrome, which could provide a useful biomarker in the future.

Five of the 39 affected people showed potential defects in S6 phosphorylation, a downstream target of PI3K/mTOR signaling. In some cases, the results suggest an upstream signaling defect in the PI3K/mTOR signaling cascade. These findings suggest that impaired PI3K/mTOR signaling as a potential disease mechanism can be detected in cell lines from people with autism spectrum disorders.

While the sample size was too small to enable a definite statement about the percentage of PI3K ‘signalopathies’ in affected people from the SSC, the experiments suggest that lymphoblastoid cell lines, which are immortalized cell lines generated from human blood lymphocytes and available from the SSC, are valid tools to reveal the specific upstream defect leading to impairments in PI3K/mTOR signaling. They may thus be useful in identifying disease-mechanism‐based drug targets for people with autism.

The researchers performed experiments in blood lymphocytes from people with fragile X syndrome to test whether defective signaling through the PI3K pathway is a biomarker for autism spectrum disorders. These analyses showed that results are most consistent in fresh blood samples that have not been shipped overnight. The results suggest that future research in optimizing these assays as biomarker tools is warranted.