Targeting TREM2 to disentangle neuroinflammation and α-Syn pathological propagation in Parkinson's disease

Parkinson's disease (PD) is a neurodegenerative disorder of the central nervous system (CNS) that predominantly affects middle-aged and elderly populations, characterized by the progressive loss of dopaminergic neurons in the substantia nigra and the abnormal aggregation of α-synuclein (α-Syn) as its core pathological features. Its pathogenesis is complex, and the crosstalk among genetic factors, microenvironmental factors and neuroinflammation has emerged as a central research focus at present. Triggering receptor expressed on myeloid cells 2 (TREM2), a key regulator of microglial function, is deeply implicated in the pathophysiological processes of PD by mediating multiple biological events, including phagocytic clearance, inflammatory homeostasis, autophagy regulation and neuronal repair. In recent years, Advances in genomics, cell biology and model animal technologies, the genetic association between TREM2 gene variants and PD, the regulatory role of the TREM2 signaling pathway in α-Syn pathological propagation, and its dual effects in neuroinflammation and dopaminergic neuron protection have been gradually elucidated. This review systematically summarizes the molecular structure and signal transduction mechanisms of TREM2, with a focus on elaborating the multidimensional roles of the TREM2 signaling pathway in the regulation of α-Syn metabolism, microglial polarization, dopaminergic neuron survival and non-motor symptoms in PD. We also conduct an in-depth analysis of the pathological significance of TREM2 gene variants and their interactive effects with microenvironmental factors, and discuss therapeutic strategies and research progress for PD targeting the TREM2 signaling pathway. Finally, we summarize the current research controversies and future directions, aiming to provide new insights into the mechanistic investigation and precision therapy of PD.