Defects in lysosomal function and lipid metabolism in human microglia harboring a TREM2 loss of function mutation

Abstract: TREM2 is an innate immune receptor expressed by microglia in the adult brain. Homozygous TREM2 mutations cause a rare leukodystrophy, Nasu-Hakola disease (NHD). Despite extensive investigation, the role of TREM2 in NHD pathogenesis remains poorly understood. Here, we investigate the mechanisms by which a homozygous stop-gain TREM2 mutation (p.Q33X) contributes to NHD. Induced pluripotent stem cell (iPSC)-derived microglia (iMGLs) were generated from two siblings homozygous for the TREM2 p.Q33X mutation (termed NHD), one related non-carrier, and one unrelated non-carrier. Transcriptomic and biochemical analyses reveal defective activation, HLA antigen presentation, and NF-kB signaling in NHD iMGLs. Additionally, NHD iMGLs exhibited lysosomal dysfunction, downregulation of cholesterol metabolism genes, and reduced lipid droplets. These defects were validated in brain tissue from NHD patients. Thus, stem cell models reveal novel dysfunctional lysosomal pathways in NHD microglia and capture pathological processes that also occur in human brains from NHD patients.