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A High-content Assay for Monitoring AMPA Receptor Trafficking
Published on: January 28, 2019
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The intellectual disability protein RAB39B selectively regulates GluA2 trafficking to determine synaptic AMPAR
Maria Lidia Mignogna1, Maila Giannandrea2, Antonia Gurgone3
11] Dulbecco Telethon Institute at IRCCS San Raffaele Scientific Institute, Division of Neuroscience, 20132 Milan, Italy [2] F. Hoffmann-La Roche AG, pRED Pharma Research &Early Development, DTA Neuroscience, CH4070 Basel, Switzerland [3] Vita-Salute San Raffaele University, 20132 Milan, Italy.
Nature Communications
|March 19, 2015
Summary
Mutations in the RAB39B gene cause intellectual disability. This study reveals RAB39B controls GluA2 surface expression, impacting synaptic activity and cognitive function in related disorders.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- RAB39B, a small GTPase, regulates intracellular trafficking.
- Mutations in RAB39B are linked to intellectual disability, autism, and epilepsy.
- The precise impact of RAB39B loss on synaptic activity remains unclear.
Purpose of the Study:
- To elucidate the downstream effectors of RAB39B.
- To investigate the role of RAB39B in regulating AMPAR composition and synaptic function.
- To understand the molecular mechanisms underlying RAB39B-related cognitive disorders.
Main Methods:
- Investigated the interaction between RAB39B and PICK1.
- Analyzed the effect of RAB39B on protein trafficking from ER to Golgi.
- Examined the surface expression of GluA2 in mouse hippocampal neurons with RAB39B downregulation.
Main Results:
- Identified PICK1 as a downstream effector of GTP-bound RAB39B.
- Demonstrated that RAB39B-PICK1 controls GluA2 trafficking and surface expression.
- Showed that RAB39B downregulation leads to Ca(2+)-permeable AMPARs and altered synaptic activity in hippocampal neurons.
Conclusions:
- RAB39B-PICK1 pathway is critical for regulating AMPAR composition.
- Altered synaptic function due to RAB39B loss may underlie cognitive deficits in related disorders.
- This study provides a molecular link between RAB39B mutations and neurological dysfunction.
