Human early-onset dementia caused by DAP12 deficiency reveals a unique signature of dysregulated microglia.
Human early-onset dementia caused by DAP12 deficiency reveals a unique signature of dysregulated microglia.
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DOI：
10.1038/s41590-022-01403-y
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发表时间：
2023-03
影响因子：
30.5
通讯作者：
Colonna, Marco
中科院分区：
文献类型：
--
作者：
Zhou, Yingyue;Tada, Mari;Cai, Zhangying;Andhey, Prabhakar S.;Swain, Amanda;Miller, Kelly R.;Gilfillan, Susan;Artyomov, Maxim N.;Takao, Masaki;Kakita, Akiyoshi;Colonna, Marco
TREM2-DAP12受体复合体支持小胶质细胞的功能。杂合性功能低下的TREM2变异会损害小胶质细胞，加速迟发性阿尔茨海默病。TREM2或TYROBP编码DAP12的纯合子失活变体会导致Nasu-Hakola病(NHD)，这是一种以脑萎缩、髓鞘丢失和胶质增生为特征的早发性痴呆。支持NHD的机制尚不清楚。在这里，对DAP12缺陷型NHD患者的脑标本进行的单核RNA-SEQ分析显示了一个独特的小胶质细胞特征，表明RUNX1、STAT3和转化生长因子β信号通路增强，介导了损伤的修复反应。这一特征与星形胶质细胞的创面愈合特征和少突胶质细胞的髓鞘损伤有关，而周细胞特征则提示血管异常。相反，缺乏DAP12信号的小鼠的单核信号反映了非常轻微的小胶质细胞缺陷，不能概括NHD。我们设想，小胶质细胞中的DAP12信号会减弱伤口愈合途径，如果不加以控制，就会干扰小胶质细胞的生理功能，导致人类的病理。识别一个失调的NHD小胶质细胞特征激发了旨在重置小胶质细胞信号通路的潜在治疗策略。
The TREM2-DAP12 receptor complex sustains microglia functions. Heterozygous hypofunctional TREM2 variants impair microglia, accelerating late-onset Alzheimer’s Disease. Homozygous inactivating variants of TREM2 or TYROBP-encoding DAP12 cause Nasu-Hakola disease (NHD), an early-onset dementia characterized by cerebral atrophy, myelin loss, and gliosis. Mechanisms underpinning NHD are unknown. Here, single-nucleus RNA-seq analysis of brain specimens from DAP12-deficient NHD individuals revealed a unique microglia signature indicating heightened RUNX1, STAT3 and TGFβ signaling pathways that mediate repair responses to injuries. This profile correlated with a wound-healing signature in astrocytes and impaired myelination in oligodendrocytes, while pericyte profiles indicated vascular abnormalities. Conversely, single-nuclei signatures in mice lacking DAP12 signaling reflected very mild microglial defects that did not recapitulate NHD. We envision that DAP12 signaling in microglia attenuates wound-healing pathways which, if left unchecked, interfere with microglial physiological functions causing pathology in human. The identification of a dysregulated NHD microglia signature sparks potential therapeutic strategies aimed at resetting microglia signaling pathways.
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影响因子：
25
作者：
Kenigsbuch, Mor;Bost, Pierre;Halevi, Shahar;Chang, Yuzhou;Chen, Shuo;Ma, Qin;Hajbi, Renana;Schwikowski, Benno;Bodenmiller, Bernd;Fu, Hongjun;Schwartz, Michal;Amit, Ido
通讯作者：
Amit, Ido
DOI：
10.1084/jem.20202717
发表时间：
2021-09-06
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Chen Y;Colonna M
通讯作者：
Colonna M
影响因子：
50.3
作者：
Hara T;Chanoch-Myers R;Mathewson ND;Myskiw C;Atta L;Bussema L;Eichhorn SW;Greenwald AC;Kinker GS;Rodman C;Gonzalez Castro LN;Wakimoto H;Rozenblatt-Rosen O;Zhuang X;Fan J;Hunter T;Verma IM;Wucherpfennig KW;Regev A;Suvà ML;Tirosh I
通讯作者：
Tirosh I
DOI：
10.1126/stke.2002.127.re3
发表时间：
2002-04-09
期刊：
Science's STKE : signal transduction knowledge environment
影响因子：
--
作者：
Griffiths, Emily K;Penninger, Josef M
通讯作者：
Penninger, Josef M
影响因子：
48
作者：
Browaeys, Robin;Saelens, Wouter;Saeys, Yvan
通讯作者：
Saeys, Yvan