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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2023
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.
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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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