Cargando…

Intracellular trafficking of TREM2 is regulated by presenilin 1

Genetic mutations in triggering receptor expressed on myeloid cells 2 (TREM2) have been linked to a variety of neurodegenerative diseases including Alzheimer’s disease, amyotrophic lateral sclerosis, frontotemporal dementia and Parkinson’s disease. In the brain, TREM2 is highly expressed on the cell...

Descripción completa

Detalles Bibliográficos
Autores principales: Zhao, Yingjun, Li, Xiaoguang, Huang, Timothy, Jiang, Lu-lin, Tan, Zhenqiu, Zhang, Muxian, Cheng, Irene Han-Juo, Wang, Xin, Bu, Guojun, Zhang, Yun-wu, Wang, Qi, Xu, Huaxi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5750471/
https://www.ncbi.nlm.nih.gov/pubmed/29611543
http://dx.doi.org/10.1038/emm.2017.200
_version_ 1783289730444558336
author Zhao, Yingjun
Li, Xiaoguang
Huang, Timothy
Jiang, Lu-lin
Tan, Zhenqiu
Zhang, Muxian
Cheng, Irene Han-Juo
Wang, Xin
Bu, Guojun
Zhang, Yun-wu
Wang, Qi
Xu, Huaxi
author_facet Zhao, Yingjun
Li, Xiaoguang
Huang, Timothy
Jiang, Lu-lin
Tan, Zhenqiu
Zhang, Muxian
Cheng, Irene Han-Juo
Wang, Xin
Bu, Guojun
Zhang, Yun-wu
Wang, Qi
Xu, Huaxi
author_sort Zhao, Yingjun
collection PubMed
description Genetic mutations in triggering receptor expressed on myeloid cells 2 (TREM2) have been linked to a variety of neurodegenerative diseases including Alzheimer’s disease, amyotrophic lateral sclerosis, frontotemporal dementia and Parkinson’s disease. In the brain, TREM2 is highly expressed on the cell surface of microglia, where it can transduce signals to regulate microglial functions such as phagocytosis. To date, mechanisms underlying intracellular trafficking of TREM2 remain elusive. Mutations in the presenilin 1 (PS1) catalytic subunit of the γ-secretase complex have been associated with increased generation of the amyloidogenic Aβ (amyloid-β) 42 peptide through cleavage of the Aβ precursor amyloid precursor protein. Here we found that TREM2 interacts with PS1 in a manner independent of γ-secretase activity. Mutations in TREM2 alter its subcellular localization and affects its interaction with PS1. Upregulation of PS1 reduces, whereas downregulation of PS1 increases, steady-state levels of cell surface TREM2. Furthermore, PS1 overexpression results in attenuated phagocytic uptake of Aβ by microglia, which is reversed by TREM2 overexpression. Our data indicate a novel role for PS1 in regulating TREM2 intracellular trafficking and pathophysiological function.
format Online
Article
Text
id pubmed-5750471
institution National Center for Biotechnology Information
language English
publishDate 2017
publisher Nature Publishing Group
record_format MEDLINE/PubMed
spelling pubmed-57504712018-01-04 Intracellular trafficking of TREM2 is regulated by presenilin 1 Zhao, Yingjun Li, Xiaoguang Huang, Timothy Jiang, Lu-lin Tan, Zhenqiu Zhang, Muxian Cheng, Irene Han-Juo Wang, Xin Bu, Guojun Zhang, Yun-wu Wang, Qi Xu, Huaxi Exp Mol Med Original Article Genetic mutations in triggering receptor expressed on myeloid cells 2 (TREM2) have been linked to a variety of neurodegenerative diseases including Alzheimer’s disease, amyotrophic lateral sclerosis, frontotemporal dementia and Parkinson’s disease. In the brain, TREM2 is highly expressed on the cell surface of microglia, where it can transduce signals to regulate microglial functions such as phagocytosis. To date, mechanisms underlying intracellular trafficking of TREM2 remain elusive. Mutations in the presenilin 1 (PS1) catalytic subunit of the γ-secretase complex have been associated with increased generation of the amyloidogenic Aβ (amyloid-β) 42 peptide through cleavage of the Aβ precursor amyloid precursor protein. Here we found that TREM2 interacts with PS1 in a manner independent of γ-secretase activity. Mutations in TREM2 alter its subcellular localization and affects its interaction with PS1. Upregulation of PS1 reduces, whereas downregulation of PS1 increases, steady-state levels of cell surface TREM2. Furthermore, PS1 overexpression results in attenuated phagocytic uptake of Aβ by microglia, which is reversed by TREM2 overexpression. Our data indicate a novel role for PS1 in regulating TREM2 intracellular trafficking and pathophysiological function. Nature Publishing Group 2017-12 2017-12-01 /pmc/articles/PMC5750471/ /pubmed/29611543 http://dx.doi.org/10.1038/emm.2017.200 Text en Copyright © 2017 The Author(s) http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Original Article
Zhao, Yingjun
Li, Xiaoguang
Huang, Timothy
Jiang, Lu-lin
Tan, Zhenqiu
Zhang, Muxian
Cheng, Irene Han-Juo
Wang, Xin
Bu, Guojun
Zhang, Yun-wu
Wang, Qi
Xu, Huaxi
Intracellular trafficking of TREM2 is regulated by presenilin 1
title Intracellular trafficking of TREM2 is regulated by presenilin 1
title_full Intracellular trafficking of TREM2 is regulated by presenilin 1
title_fullStr Intracellular trafficking of TREM2 is regulated by presenilin 1
title_full_unstemmed Intracellular trafficking of TREM2 is regulated by presenilin 1
title_short Intracellular trafficking of TREM2 is regulated by presenilin 1
title_sort intracellular trafficking of trem2 is regulated by presenilin 1
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5750471/
https://www.ncbi.nlm.nih.gov/pubmed/29611543
http://dx.doi.org/10.1038/emm.2017.200
work_keys_str_mv AT zhaoyingjun intracellulartraffickingoftrem2isregulatedbypresenilin1
AT lixiaoguang intracellulartraffickingoftrem2isregulatedbypresenilin1
AT huangtimothy intracellulartraffickingoftrem2isregulatedbypresenilin1
AT jianglulin intracellulartraffickingoftrem2isregulatedbypresenilin1
AT tanzhenqiu intracellulartraffickingoftrem2isregulatedbypresenilin1
AT zhangmuxian intracellulartraffickingoftrem2isregulatedbypresenilin1
AT chengirenehanjuo intracellulartraffickingoftrem2isregulatedbypresenilin1
AT wangxin intracellulartraffickingoftrem2isregulatedbypresenilin1
AT buguojun intracellulartraffickingoftrem2isregulatedbypresenilin1
AT zhangyunwu intracellulartraffickingoftrem2isregulatedbypresenilin1
AT wangqi intracellulartraffickingoftrem2isregulatedbypresenilin1
AT xuhuaxi intracellulartraffickingoftrem2isregulatedbypresenilin1