Increased Susceptibility and Intrinsic Apoptotic Signaling in Neurons by Induced HDAC3 Expression

Area of Science:

• Neuroscience
• Molecular Biology
• Cell Biology

Background:

• Histone deacetylase 3 (HDAC3) inhibition is neuroprotective in neurodegenerative diseases.
• HDAC3 expression in cultured cells demonstrates selective neuronal toxicity.
• The precise mechanism of HDAC3-induced neuronal pathology remains unclear.

Purpose of the Study:

• To investigate the mechanism underlying HDAC3-induced neuronal toxicity.
• To evaluate the role of HDAC3 in retinal ganglion cell (RGC) susceptibility to axonal damage.

Main Methods:

• Adeno-associated virus (AAV)-mediated gene transfer to induce HDAC3-mCherry expression in mouse RGCs.
• Assessment of RGCs' susceptibility to optic nerve crush injury.
• Evaluation of HDAC3-induced damage in 661W retinal precursor cells using immunostaining and qRT-PCR.

Main Results:

• Induced HDAC3 expression in RGCs increased sensitivity to axonal damage.
• Differentiated 661W cells expressing HDAC3 showed BAX recruitment to mitochondria and caspase 3 activation.
• HDAC3 expression upregulated transcripts for JNK2/3 kinases and the p53-regulated gene Bbc3/Puma.

Conclusions:

• HDAC3-induced neuronal toxicity is mediated by the intrinsic apoptotic pathway.
• This pathway involves mitochondrial outer membrane permeabilization and caspase activation.