TREM 2 in Parkinson's Disease: A Promising Candidate Gene for Disease Susceptibility and Progression

Abstract

Background/Objectives: The activation of microglia and the activity of innate immunity have recently been recognized as part of Parkinson's Disease (PD) pathophysiology. Triggering receptor expressed on myeloid cells 2 (TREM2) is a gene with neuroprotective roles. Its variations are associated with microglial-associated neurodegeneration. The objective of the present review is to investigate the current evidence on the role of TREM2 in PD pathophysiology. Methods: A comprehensive search was performed using PubMed, Medline, and Web of Science, looking for English papers investigating the role of TREM2 in PD, or more in general, the genetic profile of microglia. Results: Thirty-one papers were considered relevant. Preclinical studies with PD models showed some contradictory results, even if a loss of function of TREM2 is generally associated with a microglial activation in α-synuclein-induced inflammatory processes. The role for TREM2 genetic variations in PD patients should be taken with even more caution. The increase in the soluble extracellular segment of TREM2 (sTREM2) in cerebrospinal fluid of PD patients seems to be associated with increased risk of cognitive decline. Conclusions: There is increasing evidence that TREM2 may have an important role in PD pathophysiology as demonstrated by preclinical and clinical studies. Further investigations are needed to confirm this role and may lead the way for future targeted therapies for different neurodegenerative disorders.

Keywords: PD; Parkinson’s disease; TREM2; microglia; neurodegenerative disorders; neuroinflammation.

Figure 1

TREM2 expression levels could induce two distinct phenotypes in resting microglia. (a) In a scenario where TREM2 is overexpressed, its activation, mediated by one of its potential ligands (DAMPs or lipid components), promotes the phosphorylation of DAP12, a TREM2-associated transmembrane adaptor protein. This phosphorylation generates a docking site for many molecules, triggering signaling cascades that lead to the activation of SYK/PI3K/AKT/PLCγ pathway, which potentiates phagocytic activity and the regulation of PI3K/NF-κB and JAK/STAT/SOCS pathways allowing the anti-inflammatory effects. The combination of these events drives the cell toward an M2 phenotype, which has a neuroprotective function for neurons and ensures the elimination of α-synuclein aggregates [31,32]. (b) In contrast, a reduced TREM2 expression promotes the shift in microglia towards the M1 pro-inflammatory phenotype due to the lack of DAP12 phosphorylation, which causes deregulation of PI3K/NF-κB and JAK/STAT/SOCS pathways (favoring inflammatory processes) and decreased PI3K/AKT/mTOR and SYK/PI3K/AKT/PLCγ activation, leading to aberrant autophagy episodes. The final effect of these processes could damage the neurons that undergo accumulation of α-synuclein aggregates due to deregulation of phagocytosis [13,32].