Autophagy pathway alterations in lymphocytes: Potential biomarkers for autism?

Components of the mammalian target of rapamycin (mTOR) signaling pathway are key players in the pathogenesis of autism spectrum disorder (ASD). The mTOR pathway regulates protein homeostasis by promoting protein synthesis and inhibiting autophagy, a lysosomal degradation process that maintains protein quality control by breaking down cellular proteins and organelles to generate amino acids. Guomei Tang, David Sulzer and their colleagues at Columbia University Medical Center recently analyzed postmortem brain samples from individuals with ASD and discovered that, in response to hyperactive mTOR, autophagy was impaired in excitatory neurons1. In animal models, autophagy deficiency causes ASD-like synapse pathology and social behaviors.

The majority of genes that regulate autophagy are also expressed in peripheral cells. Tang, Sulzer and Veenstra-VanderWeele hypothesize that changes in autophagy genes will also be evident in the periphery, serving as valuable molecular markers of ASD. To test this idea, the team has performed a pilot study in a small cohort of individuals with ASD, designed to investigate the specificity and commonalities of molecular markers of the autophagy pathway in ASD neurons and peripheral blood cells. Preliminary findings from this study indicate that autophagy activity is impaired in the lymphoblasts of a subset of individuals with ASD, with decreased autophagy associated with low levels of key proteins that regulate autophagy induction, including AMBRA1, ULK1 and Beclin-1.

In the current project, the researchers plan to validate their findings of defects in autophagy in a larger independent set of ASD lymphoblasts, recruiting individuals from the Simon Simplex Collection (SSC). They then plan to cross-validate autophagy deficiency in an independent set of fresh peripheral blood monocytes collected from individuals with ASD and unaffected individuals recruited at the Columbia University Medical Center. Alterations in autophagy regulatory mechanisms in ASD peripheral tissue will be further confirmed in postmortem brain tissue samples from individuals with idiopathic ASD.

Successful completion of this study will result in the development of novel autophagy-based biomarkers in peripheral lymphocytes. These markers will help identify the subset of individuals with ASD in which the autophagy pathway is dysregulated, potentially leading to targeted interventions that normalize autophagy-dependent changes during childhood development when symptoms first appear.