zDHHC11 is a Common Palmitoyltransferase Regulating Microglia-Mediated Neuroinflammation across Neurodegenerative Diseases.

Purpose

Microglia-mediated neuroinflammation is a shared feature across Alzheimer's disease (AD), Parkinson's disease (PD), and diabetic cognitive impairment (DCI), but the convergent molecular mechanisms remain unclear. This study investigated whether protein S-palmitoylation serves as a common regulator of microglial neuroinflammation across distinct neurodegenerative diseases etiologies and aimed to identify the key palmitoyltransferase involved.

Methods

In vivo ND models (APP/PS1 for AD, MPTP for PD, STZ/high-fat diet for DCI) and in vitro BV2 microglial models stimulated with amyloid-β (Aβ), lipopolysaccharide (LPS), or high glucose (HG) were established. Microglial morphology, inflammatory responses, and the TLR4/MyD88 pathway were assessed by immunofluorescence, RNA-seq, RT-qPCR, and ELISA. Protein palmitoylation levels were evaluated using 2-BP and ABE assays. Palmitoyltransferase expression profiling was performed, and protein-level validation was conducted both in vitro and in vivo. Subsequently, the identified common enzyme, zDHHC11, was knocked down by siRNA to determine its functional role.

Results

All three ND models showed robust microglial activation with a pro-inflammatory amoeboid morphology. Aβ, LPS, and HG each upregulated pro-inflammatory cytokines and activated the TLR4/MyD88 pathway in BV2 cells. Palmitoylation inhibition with 2-BP attenuated cytokine production, and all three stimuli increased total protein palmitoylation. Among all palmitoyltransferases screened, zDHHC11 was uniquely and consistently upregulated by all three stimuli. This upregulation was further corroborated at the protein level, with elevated zDHHC11 expression observed both in cultured cells and in brain tissue sections. Knockdown of Zdhhc11 suppressed cytokine expression/secretion and reduced TLR4/MyD88 levels, indicating that zDHHC11 acts upstream of this common pathway.

Conclusion

Protein S-palmitoylation mediated by zDHHC11 is a convergent mechanism driving microglial pro-inflammatory activation across distinct ND etiologies. zDHHC11 represents a common regulator of TLR4/MyD88-dependent neuroinflammation and a potential therapeutic target for multiple NDs.