Shank3 protein: roles in synaptic plasticity and in autism spectrum disorder

Speaker: Menglong Zeng, Ph.D.
 Simons Postdoctoral Fellow, McGovern Institute for Brain Research, Department of Brain and Cognitive Sciences, MIT
Date: April 3, 2020

Talk title: Shank3 protein: roles in synaptic plasticity and in autism spectrum disorder  

Mutations or disruptions of the SHANK3 gene represent highly penetrant, monogenic risk factors for autism spectrum disorder (ASD) and several other neurodevelopmental disorders. In recent years, there are tremendous research efforts to establish links between the SHANK3 gene and ASD. However, our understanding about the Shank3 protein’s normal physiological function is still preliminary.

Shank3 is a master scaffold protein in the postsynaptic density (PSD) of glutamatergic synapses. It contains multiple protein-protein interaction domains, orchestrating a giant protein complex essential for normal synaptic functions. Here we identified a unique interaction between Shank3 and CaMKIIα, an abundant PSD kinase crucial for synaptic plasticity. This interaction is not present in Shank1 or Shank2, two highly homologous Shank family proteins. Our finding is interesting because human clinical analyses have shown that: (1) ASD patients with SHANK3 mutations exhibit more severe intellectual disability than SHANK1– or SHANK2-mutated ASD patients, but the underlying mechanism is unknown; (2) Mutations on CAMK2A (the gene encoded CaMKIIα) have also been identified in ASD and intellectual disability patients.

Does this unique protein interaction dictate a Shank3-specific function in synaptic plasticity? Does an impaired Shank3-CaMKIIα signaling pathway contribute to severe intellectual disability found in SHANK3-mutated ASD patients? In my talk, I will discuss our recent progresses on addressing these intriguing questions.