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

Authors Xing J, Titus A, Humphrey MB

Received 16 December 2014

Accepted for publication 29 January 2015

Published 17 March 2015 Volume 2015:5 Pages 89—100


Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 4

Editor who approved publication: Professor Nikolay Dokholyan

Junjie Xing,1,2 Amanda R Titus,1 Mary Beth Humphrey1–3

1Department of Medicine, 2Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, 3Department of Veteran's Affairs, Oklahoma City, OK, USA

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.

Keywords: polycystic, leukoencephalopathy, Alzheimer's, lipomembranous, dementia, microglia

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