Lysophosphatidic acid differentially regulates axonal mRNA translation through 5'UTR elements

Area of Science:

• Neuroscience
• Molecular Biology
• Cell Biology

Background:

• Sensory neurons transport mRNAs, including those for ER chaperone proteins, into axons.
• Calreticulin mRNA transport is regulated by 3'UTR elements, and chaperone mRNA translation can be modulated by ER stress.

Purpose of the Study:

• To investigate if axonal calreticulin mRNA translation is regulated differently from its transport.
• To determine the role of ER stress in controlling axonal calreticulin mRNA translation.

Main Methods:

• Treatment of neurons with lysophosphatidic acid to induce axon retraction and ER Ca(2+) release.
• Analysis of calreticulin protein levels and translational control mechanisms in axons.
• Investigation of the role of 5'UTR elements and eIF2α phosphorylation in translational regulation.
• Comparison with translational control of β-actin mRNA.

Main Results:

• Lysophosphatidic acid treatment increased axonal calreticulin protein levels in a translation-dependent manner.
• Specific RNA sequences in the 5'UTR of calreticulin mediate translational control.
• This control mechanism requires inactivating phosphorylation of eukaryotic initiation factor 2 alpha (eIF2α).
• The signaling pathway did not activate axonal translation of β-actin mRNA, indicating specificity.

Conclusions:

• ER stress stimulates localized mRNA translation in sensory neuron axons.
• Specificity of this localized translation is conferred by 5'UTR elements.
• The findings reveal a novel mechanism for regulating protein synthesis within neuronal axons in response to cellular stress.