The TREM2-DAP12 signaling pathway in Nasu–Hakola disease: a molecular genetics perspective

Abstract

Nasu–Hakola disease or polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL) is a rare recessively inherited disease that is associated with early dementia and bone cysts with fractures. Here, we review the genetic causes of PLOSL with loss-of-function mutations or deletions in one of two genes, TYROBP and TREM2, encoding for two proteins DNAX-activating protein 12 (DAP12) and triggering receptor expressed on myeloid cells-2 (TREM2). TREM2 and DAP12 form an immunoreceptor signaling complex that mediates myeloid cell, including microglia and osteoclasts, development, activation, and function. Functionally, TREM2-DAP12 mediates osteoclast multi-nucleation, migration, and resorption. In microglia, TREM2-DAP12 participates in recognition and apoptosis of neuronal debris and amyloid deposits. Review of the complex immunoregulatory roles of TREM2-DAP12 in the innate immune system, where it can both promote and inhibit pro-inflammatory responses, is given. Little is known about the function of TREM2-DAP12 in normal brain homeostasis or in pathological central nervous system diseases. Based on the state of the field, genetic testing now aids in diagnosis of PLOSL, but therapeutics and interventions are still under development.

An Overview of in vitro Methods to Study Microglia

“…Loss or disruption of TREM2 expression results in increased secretion of pro-inflammatory cytokines in response to various TLR ligands ( Hamerman et al, 2006 ). Interestingly, loss-of-function mutations of TREM2 cause the rare genetic disorder Nasu-Hakola disease (NHD) ( Xing et al, 2015 ). NHD is a leukodystrophy characterized by progressive presenile dementia.…”

The Early Events That Initiate β-Amyloid Aggregation in Alzheimer’s Disease

“…TREM2 associated with the adaptor proteins DNAX-activation protein 10 (DAP10) and DAP12. TREM2-DAP10-DAP12 signaling modulates the energetic cellular metabolism by activating the mechanistic target of rapamycin (mTOR; Xing et al, 2015 ). TREM2-deficient microglia showed a metabolic defect (Ulland et al, 2017 ), which may result in the microglia ineffectively responding to stressful events, such as Aβ toxicity.…”

Humanized TREM2 mice reveal microglia-intrinsic and -extrinsic effects of R47H polymorphism

“…In vitro, TREM2 binds anionic lipids ( Wang et al, 2015 ), lipidated ApoE and ApoJ ( Atagi et al, 2015 ; Bailey et al, 2015 ), high-density and low-density lipoproteins ( Yeh et al, 2016 ; Song et al, 2017 ), and apoptotic cells ( Hsieh et al, 2009 ), but in vivo ligands are not known. Engagement of TREM2 by ligands activates downstream protein tyrosine phosphorylation through its adaptor DAP12 ( Xing et al, 2015 ), stimulating mTOR signaling, energetic and anabolic metabolism ( Ulland et al, 2017 ), proliferation, and survival ( Otero et al, 2009 ) while suppressing TLR-induced inflammatory cytokine production ( Hamerman et al, 2006 ; Turnbull et al, 2006 ). TREM2 is also shed from the cell surface by metalloproteinases such as Adam10 and Adam17 and released as a soluble protein ( Wunderlich et al, 2013 ; Kleinberger et al, 2014 ; Feuerbach et al, 2017 ), which has been proposed to mediate cell survival and inflammation ( Wu et al, 2015 ; Zhong et al, 2017 ).…”