Microglial activation-induced neuroinflammation is a key process in Parkinson's disease (PD), but the relevant cellular state and the regulatory capacity of gut-derived short-chain fatty acids (SCFAs) remain incompletely resolved. In this study, bulk transcriptomic analysis of the substantia nigra was combined with single-nucleus transcriptomic profiling of the midbrain to examine PD-associated microglial activation and to evaluate the proposed SCFA-HDAC pathway. Pathway-level analysis showed downregulation of dopaminergic and synaptic pathways with concomitant upregulation of neuroinflammatory pathways. Single-nucleus analysis localized this signal to a glycoprotein non-metastatic melanoma protein B (GPNMB)-positive disease-associated microglia (DAM)-like activated subcluster that was consistently enriched in PD donors within this cohort. Using perturbation connectivity analysis and molecular docking, the present computational proxy assessment did not support a uniform reversal of this activation program by HDAC inhibition, and regulation of the core target GPNMB was drug-specific rather than uniform. These findings identify a candidate GPNMB-positive activated microglial phenotype associated with PD neuroinflammation and indicate that support for the proposed SCFA-HDAC axis is limited under the present evidence.