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Causal ALS genes impact the MHC class II antigen presentation pathway
Mutations in RNA/DNA-binding proteins cause amyotrophic lateral sclerosis (ALS), but the underlying disease mechanisms remain unclear. Here, we report that a set of ALS-associated proteins, namely FUS, EWSR1, TAF15, and MATR3, impact the expression of genes encoding the major histocompatibility comp...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
National Academy of Sciences
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10523463/ https://www.ncbi.nlm.nih.gov/pubmed/37722062 http://dx.doi.org/10.1073/pnas.2305756120 |
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author | Chi, Binkai Öztürk, Muhammet M. Paraggio, Christina L. Leonard, Claudia E. Sanita, Maria E. Dastpak, Mahtab O’Connell, Jeremy D. Coady, Jordan A. Zhang, Jiuchun Gygi, Steven P. Lopez-Gonzalez, Rodrigo Yin, Shanye Reed, Robin |
author_facet | Chi, Binkai Öztürk, Muhammet M. Paraggio, Christina L. Leonard, Claudia E. Sanita, Maria E. Dastpak, Mahtab O’Connell, Jeremy D. Coady, Jordan A. Zhang, Jiuchun Gygi, Steven P. Lopez-Gonzalez, Rodrigo Yin, Shanye Reed, Robin |
author_sort | Chi, Binkai |
collection | PubMed |
description | Mutations in RNA/DNA-binding proteins cause amyotrophic lateral sclerosis (ALS), but the underlying disease mechanisms remain unclear. Here, we report that a set of ALS-associated proteins, namely FUS, EWSR1, TAF15, and MATR3, impact the expression of genes encoding the major histocompatibility complex II (MHC II) antigen presentation pathway. Both subunits of the MHC II heterodimer, HLA-DR, are down-regulated in ALS gene knockouts/knockdown in HeLa and human microglial cells, due to loss of the MHC II transcription factor CIITA. Importantly, hematopoietic progenitor cells (HPCs) derived from human embryonic stem cells bearing the FUS(R495X) mutation and HPCs derived from C9ORF72 ALS patient induced pluripotent stem cells also exhibit disrupted MHC II expression. Given that HPCs give rise to numerous immune cells, our data raise the possibility that loss of the MHC II pathway results in global failure of the immune system to protect motor neurons from damage that leads to ALS. |
format | Online Article Text |
id | pubmed-10523463 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | National Academy of Sciences |
record_format | MEDLINE/PubMed |
spelling | pubmed-105234632023-09-28 Causal ALS genes impact the MHC class II antigen presentation pathway Chi, Binkai Öztürk, Muhammet M. Paraggio, Christina L. Leonard, Claudia E. Sanita, Maria E. Dastpak, Mahtab O’Connell, Jeremy D. Coady, Jordan A. Zhang, Jiuchun Gygi, Steven P. Lopez-Gonzalez, Rodrigo Yin, Shanye Reed, Robin Proc Natl Acad Sci U S A Biological Sciences Mutations in RNA/DNA-binding proteins cause amyotrophic lateral sclerosis (ALS), but the underlying disease mechanisms remain unclear. Here, we report that a set of ALS-associated proteins, namely FUS, EWSR1, TAF15, and MATR3, impact the expression of genes encoding the major histocompatibility complex II (MHC II) antigen presentation pathway. Both subunits of the MHC II heterodimer, HLA-DR, are down-regulated in ALS gene knockouts/knockdown in HeLa and human microglial cells, due to loss of the MHC II transcription factor CIITA. Importantly, hematopoietic progenitor cells (HPCs) derived from human embryonic stem cells bearing the FUS(R495X) mutation and HPCs derived from C9ORF72 ALS patient induced pluripotent stem cells also exhibit disrupted MHC II expression. Given that HPCs give rise to numerous immune cells, our data raise the possibility that loss of the MHC II pathway results in global failure of the immune system to protect motor neurons from damage that leads to ALS. National Academy of Sciences 2023-09-18 2023-09-26 /pmc/articles/PMC10523463/ /pubmed/37722062 http://dx.doi.org/10.1073/pnas.2305756120 Text en Copyright © 2023 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by/4.0/This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY) (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Biological Sciences Chi, Binkai Öztürk, Muhammet M. Paraggio, Christina L. Leonard, Claudia E. Sanita, Maria E. Dastpak, Mahtab O’Connell, Jeremy D. Coady, Jordan A. Zhang, Jiuchun Gygi, Steven P. Lopez-Gonzalez, Rodrigo Yin, Shanye Reed, Robin Causal ALS genes impact the MHC class II antigen presentation pathway |
title | Causal ALS genes impact the MHC class II antigen presentation pathway |
title_full | Causal ALS genes impact the MHC class II antigen presentation pathway |
title_fullStr | Causal ALS genes impact the MHC class II antigen presentation pathway |
title_full_unstemmed | Causal ALS genes impact the MHC class II antigen presentation pathway |
title_short | Causal ALS genes impact the MHC class II antigen presentation pathway |
title_sort | causal als genes impact the mhc class ii antigen presentation pathway |
topic | Biological Sciences |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10523463/ https://www.ncbi.nlm.nih.gov/pubmed/37722062 http://dx.doi.org/10.1073/pnas.2305756120 |
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