Updated project metadata. Synaptic dysfunction may underlie the pathophysiology of Parkinson’s disease (PD): a presently incurable condition characterized by motor and cognitive symptoms. Here we used quantitative proteomics to study the role of PHF8, a chromatin-modifying enzyme found to be mutated in intellectual disability, in regulating the expression of synaptic plasticity-related proteins, amongst which the Parkinson’s disease-associated alpha synuclein (SNCA) and its interactors including CamKIIa, CPLX1, RPH3A, CALB1, CHN1 were prominently featured. Depletion of PHF8 in cortical neurons affected the activity-induced expression of proteins involved in synaptic plasticity, synaptic structure, vesicular release and membrane trafficking, spanning the spectrum of pre-synaptic and post-synaptic transmission. By showing how the depletion of one chromatin-modifying enzyme can affect synaptic function in a concerted manner, we propose the possibility of targeting PHF8 as a potential disease-modifying therapeutic drug target in PD.