Role of LIN28/let-7 axis in autism

Disruption in the number and function of brain synapses — the connections between neurons — is a central feature in the development of autism and associated cognitive disabilities. Although our understanding of how brain development differs in autism is not complete, an early overgrowth of neurons and synapses, as well as a failure to prune inappropriate synapses, has been observed in the brains of children with autism and in autism mouse models. At the molecular level, overproduction of key synaptic proteins may contribute to the atypical neural and synaptic growth in autism.

In 2012, Mollie Meffert and her colleagues at the Johns Hopkins University School of Medicine in Baltimore elucidated the role of an RNA-binding protein called LIN28 in protein synthesis that supports growth in neurons. LIN28 downregulates certain microRNAs (miRNAs), or small fragments of RNA, including let-7 miRNAs, which are known to suppress many pro-growth genes. Reduction of let-7 miRNA levels by LIN28 allows synthesis of these pro-growth genes, which include synaptic proteins linked to autism.

Meffert’s team plans to investigate how LIN28 and let-7 may be pathologically regulated in autism, leading to an overabundance of pro-growth proteins. The researchers are using mouse models to investigate the molecular mechanisms that might lead to aberrant levels of LIN28. This work may ultimately reveal new potential avenues for therapeutic intervention in autism.