Impaired function of HDAC6 slows down axonal growth and interferes with axon initial segment development

Area of Science:

• Neuroscience
• Cell Biology
• Molecular Biology

Background:

• Neuronal polarity development involves axon formation and the establishment of the axon initial segment (AIS).
• The AIS acts as a diffusion barrier, concentrating key proteins for neuronal function.
• Microtubule cytoskeleton regulation during axon elongation and AIS formation is not fully understood.

Purpose of the Study:

• To investigate the role of the tubulin deacetylase HDAC6 in neuronal polarity and axon development.
• To understand how HDAC6 influences microtubule characteristics and protein localization at the AIS.

Main Methods:

• Studies were conducted in murine cultured hippocampal neurons.
• HDAC6 activity was inhibited using TSA or tubacin.
• HDAC6 expression was suppressed using shRNAs or a non-active mutant.
• Detergent treatments were used to analyze microtubule stability and acetylation.

Main Results:

• HDAC6 localizes to the distal axon and its inhibition/suppression reduces axonal length.
• HDAC6 inhibition/suppression prevents the concentration of ankyrinG and sodium channels at the AIS.
• A pool of acetylated microtubules was identified at the AIS, resistant to detergents.
• HDAC6 inhibition increases axonal acetylation and disrupts AIS cytoskeleton specificity, altering KIF5C localization.

Conclusions:

• HDAC6 acts as a regulator of microtubule characteristics in the distal axon, impacting axonal elongation.
• HDAC6 activity is crucial for establishing specific microtubule microdomains, such as the acetylated AIS.