Shank3 modulates Rpl3 expression and protein synthesis via mGlu5: implications for Phelan McDermid syndrome

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• SHANK3 gene mutations are linked to autism spectrum disorder (ASD) and Phelan McDermid syndrome (PMS).
• Synaptic dysfunction is a known consequence of Shank3 deficiency.
• Mechanisms beyond synaptic function affected by Shank3 are not well understood.

Purpose of the Study:

• To investigate novel mechanisms of Shank3 in regulating neuronal function.
• To explore the role of protein synthesis in Shank3-associated neurodevelopmental disorders.
• To identify potential therapeutic targets for Shank3-related conditions.

Main Methods:

• Utilized Shank3 knockout (KO) mouse models and human-induced pluripotent stem cells (hiPSCs) from PMS patients.
• Assessed ribosomal protein Rpl3 expression and global protein synthesis in neuronal tissues.
• Investigated the effects of mGlu5 receptor modulation on Rpl3 expression and protein synthesis.
• Evaluated behavioral outcomes in Shank3 KO mice following therapeutic interventions.

Main Results:

• Shank3 deficiency led to downregulated Rpl3 and impaired protein synthesis in mouse and human neuronal models.
• Restoring Rpl3 expression in Shank3 KO mice rescued protein synthesis and reduced behavioral abnormalities like excessive grooming.
• Inhibition of mGlu5 receptor reduced Rpl3 expression and protein synthesis.
• Treatment with an mGlu5 positive allosteric modulator (VU0409551) reversed Rpl3 downregulation, restored protein synthesis, and improved behavioral deficits.

Conclusions:

• Shank3 plays a critical role in regulating ribosomal protein Rpl3 expression and overall protein synthesis.
• Downregulation of Rpl3 and impaired protein synthesis contribute to behavioral deficits in Shank3 deficiency.
• Modulating mGlu5 receptor activity represents a promising therapeutic strategy for Shank3-related disorders.