The Double-Edged Sword: A Structured Narrative Review of Microglial Phenotypic Transition as a Pivotal Driver and Therapeutic Target in Parkinson's Disease.

OBJECTIVE

Parkinson's disease (PD) is a progressive neurodegenerative disorder primarily involving the loss of dopaminergic neurons and pathological α-synuclein (α-syn) aggregation. A pivotal feature of PD pathogenesis is the dual role of microglia, which shifts from maintaining neuronal homeostasis to driving neuroinflammation and neurodegeneration. The mechanisms underlying this functional transition and its consequences for disease progression require a comprehensive synthesis.

METHODS

A structured PubMed search was performed using the keywords "Parkinson's disease", "microglia", "neuroinflammation", "α-synuclein", "polarization", "tunneling nanotubes (TNTs)", "NF-κB", and "NLRP3". Relevant combinations of these terms were also used. A total of 2952 records were retrieved up to December 2025. Of these, 147 studies were included based on relevance to microglial polarization, neuroinflammation, α-syn-related pathology, and intercellular communication mechanisms.

RESULTS

In early PD stages, microglia exert neuroprotective effects by transferring excess neuronal α-syn via TNTs, delivering healthy mitochondria, and clearing α-syn through autophagy. With disease progression, accumulated α-syn promotes microglial polarization toward the M1 phenotype. This shift activates TLR2/4, TREM2, MHCII, and RAGE receptors, triggering NF-κB/NLRP3 pathways, releasing pro-inflammatory cytokines, and generating NOX2-derived ROS. The resulting neuroinflammatory cascade not only damages dopaminergic neurons directly but also disrupts astrocyte function and blood-brain barrier integrity, creating a self-perpetuating cycle of inflammation and neurodegeneration.

DISCUSSION: These findings support dysregulated microglial polarization as an important component of PD pathobiology, but the available evidence remains weighted toward preclinical models. Future work should better define the timing, heterogeneity, and clinical measurability of microglial state transitions before microglia-targeted strategies can be translated with confidence.

CONCLUSION

Microglial polarization may represent a potential therapeutic direction in Parkinson's disease, although further mechanistic and clinical validation and more precise biomarker definition remain necessary.