A novel mutation in TREM2 gene causing Nasu-Hakola disease and review of the literature

Dardiotis, Efthimios; Siokas, Vasileios; Pantazi, Eva; Dardioti, Maria; Rikos, Dimitrios; Xiromerisiou, Georgia; Markou, Aikaterini; Papadimitriou, Dimitra; Speletas, Matthaios; Hadjigeorgiou, Georgios M.

doi:10.1016/j.neurobiolaging.2017.01.015

Cited by 73 publications

(61 citation statements)

References 34 publications

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“…• AD risk allele Jonsson et al, 2012). • Mutations linked to NHD, FTD, PD, and ALS (Dardiotis et al, 2017;Yeh et al, 2017). • Phagocytosis receptor for Aβ plaques by means of APOE (Atagi et al, 2015;Bailey et al, 2015;Yeh et al, 2017).…”

Section: Trem2/ Tyrobpmentioning

confidence: 99%

Developmental roles of microglia: A window into mechanisms of disease

Anderson

Vetter

2018

Developmental Dynamics

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Microglia are engineers of the CNS both in health and disease. In addition to the canonical immunological roles of clearing damaging entities and limiting the spread of toxicity and death, microglia remodel the CNS throughout life. While they have been extensively studied in disease and injury, due to their highly variable functions, their precise role in these contexts still remains uncertain. Over the last decade we have greatly expanded our understanding of microglial function, including their essential homeostatic roles during development. Here, we review these developmental roles, identify parallels in disease, and speculate whether developmental mechanisms reemerge in disease and injury.

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Section: Trem2/ Tyrobpmentioning

confidence: 99%

Developmental roles of microglia: A window into mechanisms of disease

Anderson

Vetter

2018

Developmental Dynamics

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“…of which is characterized by demyelination, early-onset dementia, and bone cyst lipoma and known to be associated with Y38C, W50C, T66M, and V126G mutations in the ectodomains of TREM2 [22][23][24][25] .…”

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confidence: 99%

Mechanistic insights into the deleterious roles of Nasu-Hakola disease associated TREM2 variants

Dash

Choi

Moon

2020

Sci Rep

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Recently, the critical roles played by genetic variants of TREM2 (Triggering Receptor Expressed on Myeloid cells 2) in Alzheimer's disease have been aggressively highlighted. However, few studies have focused on the deleterious roles of Nasu-Hakola disease (NHD) associated TREM2 variants. In order to get insights into the contributions made by these variants to neurodegeneration, we investigated the influences of four NHD associated TREM2 mutations (Y38C, W50C, T66M, and V126G) on loss-offunction, and followed this with in silico prediction and conventional molecular dynamics simulation. NHD mutations were predicted to be highly deleterious by eight different in silico bioinformatics tools and found to induce conformational changes by molecular dynamics simulation. As compared with the wild-type, the four variants produced substantial differences in the collective motions of loop regions, which not only promoted structural remodeling in the CDR2 (complementarity-determining region 2) loop but also in the CDR1 loop, by changing inter-and intra-loop hydrogen bonding networks. In addition, structural studies in a free energy landscape analysis showed that Y38, T66, and V126 are crucial for maintaining the structural features of CDR1 and CDR2 loops, and that mutations in these positions produced steric clashes and loss of ligand binding. These results showed the presence of mutations in the TREM2 ectodomain induced flexibility and caused structural alterations. Dynamical scenarios, as provided by the present study, may be critical to our understanding of the roles of these TREM2 mutations in neurodegenerative diseases. The accumulation of amyloid-β (Aβ) in brain parenchyma is the main hallmark of Alzheimer's disease (AD), which results in a slow progressive decline of cognitive function by causing the formation of intracellular neurofibrillary tangles, synapse loss, and cell death 1,2. Although the precise mechanisms and molecular determinants of this neurodegenerative disease are incomplete, recent whole-genome sequencing studies have demonstrated altered genetic loci including those in TREM2 (Triggering Receptor Expressed on Myeloid cells 2) are associated with a markedly higher risk of progression to AD 3,4. TREM2 is a V-type immunoglobulin (Ig) domain-containing transmembrane protein that is expressed in osteoclasts, microglia, alveolar macrophages, and other mononuclear phagocytes 4. The activation of TREM2 is initiated by anionic lipids, such as bacterial lipopolysaccharide (LPS) and phospholipids, and several putative ligands like apolipoprotein J (ApoJ) and apolipoprotein E (ApoE) have been reported to bind to TREM2 5-7. Upon ligand binding, TREM2 recruits protein tyrosine kinase SYK through an adapter protein known as DNAX-activating protein of 12 kDa (DAP12), which interacts with the transmembrane region of TREM2 8-10. This binding is followed by a cascade of signaling events, which include the activations of MAPK and PI3K, and regulates the phagocytosis of cellular debris and the inflammatory responses of ...

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“…TYROBP was identified as a key driver in late onset AD 9 . TREM2 binds to TYROBP, its intracellular adaptor, to initiate its signal transduction pathway, and naturally occurring loss-of-function mutations of either TYROBP or TREM2 can lead to Nasu-Hakola disease 13,34 . There is a general assumption among investigators in this research area that genetic deletion or overexpression of either TREM2 or TYROBP would result in identical phenotypes in disease models, but, until now, this has not been tested directly.…”

Section: Discussionmentioning

confidence: 99%

Reactive or transgenic increase in microglial TYROBP reveals a TREM2-independent TYROBP-APOE link in wild-type and Alzheimer’s-related mice

Audrain

Haure‐Mirande

Mleczko

et al. 2020

Preprint

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Microglial TYROBP (also known as DAP12) has been identified by computational transcriptomics as a network hub and driver in late-onset sporadic Alzheimer's disease (AD) and as an important regulator of the microglial environmental sensing function. TYROBP is the transmembrane adaptor of AD-related receptors TREM2 and CR3, but importantly, TYROBP interacts with many other receptors, and little is known about its roles in microglial action and/or in the pathogenesis of AD. Herein, using dual RNA in situ hybridization and immunohistochemistry, we demonstrate that endogenous Tyrobp transcription is increased specifically in recruited microglia in the brains of wild-type and AD-related mouse models. To determine whether chronically elevated TYROBP might modify microglial phenotype and/or progression of AD pathogenesis, we generated a novel transgenic mouse overexpressing TYROBP in microglia. TYROBP-overexpressing mice were crossed with either APP/PSEN1 or MAPTP301S mice, resulting in a decrease of the amyloid burden in the former and an increase of TAU phosphorylation in the latter. Apolipoprotein E (Apoe) transcription was upregulated in MAPTP301S mice overexpressing TYROBP and transcription of genes previously associated with Apoe, including Axl, Ccl2, Tgfb and Il6, was altered in both APP/PSEN1 and MAPTP301S mice overexpressing TYROBP. Lastly, Tyrobp and Apoe mRNAs were clearly increased in Trem2-null mice in microglia recruited around a cortical stab injury or amyloid-beta deposits. Conversely, microglial Apoe mRNA level was dramatically diminished when Tyrobp was absent. Our results provide compelling evidence that TYROBP-APOE signaling in the microglial sensome does not require TREM2. We propose that activation of a TREM2-independent TYROBP-APOE signaling could be an early or even initiating step in the transformation of microglia from the homeostatic phenotype to the Disease-Associated Microglia (DAM) phenotype.

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A novel mutation in TREM2 gene causing Nasu-Hakola disease and review of the literature

Cited by 73 publications

References 34 publications

Developmental roles of microglia: A window into mechanisms of disease

Developmental roles of microglia: A window into mechanisms of disease

Mechanistic insights into the deleterious roles of Nasu-Hakola disease associated TREM2 variants

Reactive or transgenic increase in microglial TYROBP reveals a TREM2-independent TYROBP-APOE link in wild-type and Alzheimer’s-related mice

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