Functional characterization of hiPSCs-derived glial cells and neurons from patients harboring a TREM2 loss of function mutation.

BACKGROUND: Triggering receptor expressed on myeloid cells 2 (TREM2) is an innate immune receptor expressed by microglia in the adult brain. Homozygous loss of function TREM2 variants cause a rare leukodystrophy characterized by bone cysts and early-onset dementia, Nasu-Hakola disease (NHD). However, despite intense investigation, the role of TREM2 in NHD pathogenesis remains poorly understood.

METHOD: Here, we investigated the mechanisms by which a homozygous stop-gain TREM2 variant (Q33X), which leads to a truncated TREM2 transcript, contributes to disease pathology in NHD. Human induced pluripotent stem cells (hiPSCs)-derived microglia (iMGLs), neurons and astrocytes were obtained from two siblings homozygous for the TREM2 Q33X mutation and one non-carrier sibling.

RESULT: Transcriptomic analysis and biochemical assays revealed that iMGLs from NHD patients display decreased activation, reduced lipid droplet content and defects in lysosomal function compared to related and unrelated controls. These in vitro findings were validated in brain tissues from NHD patients carrying loss of function TREM2 mutations. Strikingly, we observed defects beyond iMGLs. iPSCs-derived neurons and astrocytes from NHD siblings displayed downregulation of pathways involved in synaptic activation, neuronal development and interferon response compared to the unaffected sibling. These pathways were also observed to be similarly altered in NHD brains. This could be due to the presence of low levels of mutant TREM2 transcripts in iPSC and neural progenitor cells, which may initiate a cascade of events that drives cellular dysfunction beyond microglia.

CONCLUSION: These finding open a new scenario on TREM2 function and reveal that NHD is a complex pathology affecting glial cells and neurons at multiple levels.