Brain-Region-Specific Differences in Protein Citrullination/Deimination in a Pre-Motor Parkinson's Disease Rat Model.

Area of Science:

• Neuroscience
• Biochemistry
• Molecular Biology

Background:

• Parkinson's disease (PD) early molecular mechanisms and biomarkers are challenging to detect.
• Post-translational citrullination by peptidylarginine deiminases (PADs) is implicated in early PD stages.
• PADs are calcium-activated enzymes.

Purpose of the Study:

• To assess brain-region-specific citrullinated protein targets in a pre-motor Parkinson's disease (PD) rat model.
• To analyze protein-protein interaction networks and PAD isozymes in relation to citrullination.
• To identify early molecular changes in PD.

Main Methods:

• Used a 6-hydroxydopamine (6-OHDA) induced rat model of pre-motor PD.
• Compared six brain regions (cortex, hippocampus, striatum, midbrain, cerebellum, olfactory bulb) between controls and the PD model.
• Performed citrullinome-associated pathway enrichment analysis and assessed PAD isozyme expression.

Main Results:

• Significant differences in citrullinated protein IDs were found in all brain regions between PD model and controls.
• Citrullinated proteins were most abundant in the cortex and hippocampus.
• Pathway analysis revealed PD-specific neurological, metabolic, immune, and hormonal pathways, with observed brain-region-specific differences in PAD isozymes (PAD 2, 3, and 4 showing most changes).

Conclusions:

• PAD-mediated protein citrullination is involved in metabolic, immune, cell signaling, and neurodegenerative pathways in early pre-motor PD.
• These findings highlight PADs as potential therapeutic targets for early PD intervention.
• Brain-region-specific citrullination patterns offer insights into PD pathogenesis.