Altered histone acetylation patterns reported in Parkinson’s Disease (PD) pathology suggest histone deacetylase (HDAC) inhibition may be a disease-modifying therapy. However, which HDACs should be targeted for neuroprotection is unclear. We investigated effects of class-IIa HDAC inhibition using; 1)A small molecule class-IIa HDAC inhibitor, TMP269, hypothesising TMP269 protects dopaminergic (DA) neurons against degeneration from DA neurotoxin 6-hydroxydopamine (6-OHDA), and 2)RNA inhibition (RNAi) of HDAC9, hypothesising HDAC9 inhibition protects DA neurons against alpha-synuclein (α-syn) induced degeneration. Treatment with 0.01uM TMP269 protected the SH-SY5Y cell line and primary DA cultures against 6-OHDA-induced degeneration in vitro. In vivo, peripheral administration of 0.5mg/kg of TMP269 daily over a 7-day period post-surgery protected Sprague-Dawley rats against DA neuronal degeneration from 20µg intra-striatally injected 6-OHDA, and partially protected against 6-OHDA-induced motor deficits at 12 days post-surgery.siRNA inhibition of HDAC9 in vitro protected SH-SY5Y cells against a-syn-induced degeneration. In vivo, intra-nigral injection of AAV-shHDAC9 protected DA neurons in Sprague-Dawley rats against degeneration induced by intra-nigral AAV-α-syn at 24 weeks post-surgery. HDAC9 inhibition also reduced microglial number in substantia nigra and striatum.In terms of mechanisms, the neuroprotective BMP-Smad signalling pathway has been reported as a regulatory target of class-IIa HDACs. Using a GFP-based transcriptional reporter showed both TMP269 treatment, and siRNA inhibition of HDAC9 increased Smad-dependent transcription.Overall, we’ve shown pharmacological- and RNAi-mediated inhibition of class-IIa HDACs protects DA neurons against degeneration, and activates the protective BMP-Smad signalling pathway, important first steps in evaluating the potential of class-IIa inhibition as an effective PD therapy.