Neurodegenerative disease mutations in TREM2 reveal a functional surface and distinct loss-of-function mechanisms

Abstract

Genetic variations in the myeloid immune receptor TREM2 are linked to several neurodegenerative diseases. To determine how TREM2 variants contribute to these diseases, we performed structural and functional studies of wild-type and variant proteins. Our 3.1 Å TREM2 crystal structure revealed that mutations found in Nasu-Hakola disease are buried whereas Alzheimer’s disease risk variants are found on the surface, suggesting that these mutations have distinct effects on TREM2 function. Biophysical and cellular methods indicate that Nasu-Hakola mutations impact protein stability and decrease folded TREM2 surface expression, whereas Alzheimer’s risk variants impact binding to a TREM2 ligand. Additionally, the Alzheimer’s risk variants appear to epitope map a functional surface on TREM2 that is unique within the larger TREM family. These findings provide a guide to structural and functional differences among genetic variants of TREM2, indicating that therapies targeting the TREM2 pathway should be tailored to these genetic and functional differences with patient-specific medicine approaches for neurodegenerative disorders.DOI: http://dx.doi.org/10.7554/eLife.20391.001

TREM2, Microglia, and Neurodegenerative Diseases

“…A crystal structure of TREM2 also found a potential phospholipid binding site that is largely consistent with the model structure shown [120]. In addition, the authors concluded that residues mutated in NHD were buried and could impact [ 5 6 9 _ T D $ D I F F ] protein folding, while the AD-associated residues were found on the surface and could affect ligand binding [120]. longer encodes a transmembrane (TM) domain, producing a TREM2 protein that is presumed to be soluble and secreted.…”

“…The putative structure of the TREM2 Ig-like domain showed that there is a prominent patch of hydrophobic amino acids with adjacent positively charged residues, a potential binding pocket for phospholipids, that by contrast was not found on the surface of TREM1 -which does not interact with phospholipids [117] (Figure 5). A crystal structure of TREM2 also found a potential phospholipid binding site that is largely consistent with the model structure shown [120]. In addition, the authors concluded that residues mutated in NHD were buried and could impact [ 5 6 9 _ T D $ D I F F ] protein folding, while the AD-associated residues were found on the surface and could affect ligand binding [120].…”

TREM2-Ligand Interactions in Health and Disease

“…The association of distinct variants with different diseases is born out on the protein level. Structural, biophysical, and cellular studies have shown the NHD coding mutants are misfolded with immature glycosylation patterns while the AD variants are properly folded and have mature glycosylation patterns but likely impact ligand binding [25, 26] (Fig 1C and Table 2). Slightly altered glycosylation patterns have been observed for the R47H variant [27, 28], but it is unclear if these have functional ramifications.…”

“…Pathway analysis identified the TREM2 co-receptor DAP12 as a key regulator of expression changes in LOAD [35]. Although there have been reports of TREM2 detection on non-myeloid/microglial cells in the CNS [4, 36], these cases have largely used immunostaining methods to identify neuronal expression of TREM2, which may identify sTREM2 produced by microglia that is released and bound to neurons which express a TREM2 ligand [26, 37–39]. RNA expression analyses have confirmed Trem2 is expressed selectively on microglia in the brain [40, 41], and parabiosis experiments show these microglia are most likely resident microglia and not infiltrating monocytes [42], although this is still controversial [43].…”

A Novel TREM2-Mediated Link between Diabetes and Cognitive Impairment: Recent Findings and Future Perspectives

“…Recent accumulating evidence reveals an association between a diverse array of TREM2 variants and risk for AD and other neurodegenerative diseases [10][11][12]. These variants include mutations affecting TREM2 structure/function such as the generation of a truncated protein (W44X or W78X variants) [21], inability to associate with its intracellular adaptor, DAP12/TYROBP (K186N variant) [21], reduction in ligand binding ability (R47H variant) [22][23][24], alteration of subcellular localization (reduction on cell surface and increase in endoplasmic reticulum in T66M or Y38C variants) [18,25] and accelerated proteolytic loss from the cell surface (H157Y variant) [19,20]. Therefore, TREM2-related microglial dysfunction can potentially lead to the impairment of brain homeostasis including amyloid-β clearance, possibly leading to neuronal injury and cognitive dysfunction.…”