Histone deacetylases in axonal growth and regeneration and their relevance to Parkinson's disease.

Abstract

Functional decline in Parkinson's disease (PD) is the cumulative result of regulatory alterations affecting large numbers of genes involved in various aspects of neuronal maintenance and function, and it has recently emerged that axonal degeneration plays a key role. Central to the alterations in gene expression that underlie this failure of axon maintenance, is the regulation of gene transcription by enzymes known as histone deacetylases (HDAC) which promote the de‐acetylation of histone proteins to inhibit transcription. alpha‐synuclein, a key protein that accumulates in the brains of patients with the disease, binds histone proteins in vitro & in vivo, and nuclear a‐synuclein reduces acetylated histone 3 (AcH3) levels. However while these molecular insights are important, how they regulate the neuronal structure and axonal growth in neurons affected by Parkinson's, and the relevance of this cell biology approach to the human brain is unknown.Here we used a network approach to identify all genes that had a significant positive (r+) or negative (r−) correlation with the expression of all HDACs using microarray data from the human substantia nigra (SN; GSE 60863). We then conducted a detailed enrichment analysis to identify biological pathways that were over‐represented and may be linked to Parkinson's Disease. These analyses showed that Class‐II but not Class‐I HDACs were significantly correlated with functional pathways linked to Parkinson's Disease (p<0.0001). These included genes linked to familial Parkinson's Disease and oxidative phosphorylation, including those associated with mitochondrial complex I.To link these data with changes in neuronal structure, we next examined the effects of class specific HDAC inhibitors on neuronal structure by examining a range of HDAC inhibitors for their ability to promote axonal growth and branching in dopaminergic and sympathetic neurons which are the two main cell types that undergo progressive axonal degeneration in Parkinson's Disease. We found that a MC1568 (a class II inhibitor) but not MS275 (a class I inhibitor) promoted significant increases in axon growth and branching (p<0.01). Therefore we further examined the therapeutic potential of MC1568, and found it protected against the detrimental effects of MPP+‐ and alpha‐synuclein induced axonal degeneration in a models of Parkinson's disease.This study therefore provides new insights into the regulator mechanisms that control axonal growth in neurons affects by Parkinson's, and highlights the potential of using this approach to identify therapeutic targets for neuroprotection and axonal regeneration.Support or Funding InformationThis work was funded by a Career Development Award from Science Foundation Ireland under the grant number 15/CDA/3498.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.