Causal ALS genes impact the MHC class II antigen presentation pathway

Binkai Chi; Muhammet M. Öztürk; Christina L. Paraggio; Claudia E. Leonard; Maria E. Sanita; Mahtab Dastpak; Jeremy D. O’Connell; Jordan A. Coady; Jiuchun Zhang; Steven P. Gygi; Rodrigo Lopez-Gonzalez; Shanye Yin; Robin Reed

doi:10.1073/pnas.2305756120

Causal ALS genes impact the MHC class II antigen presentation pathway

Binkai Chi, Muhammet M. Öztürk, Christina L. Paraggio, Claudia E. Leonard, Maria E. Sanita, Mahtab Dastpak, Jeremy D. O’Connell, Jordan A. Coady, Jiuchun Zhang, Steven P. Gygi, Rodrigo Lopez-Gonzalez, Shanye Yin, Robin Reed

Pathology

Research output: Contribution to journal › Article › peer-review

1 Scopus citations

Abstract

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.

Original language	English (US)
Article number	e2305756120
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	120
Issue number	39
DOIs	https://doi.org/10.1073/pnas.2305756120
State	Published - 2023

Keywords

ALS | FUS | C9ORF72 | MHC II

ASJC Scopus subject areas

General

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1073/pnas.2305756120

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Chi, B., Öztürk, M. M., Paraggio, C. L., Leonard, C. E., Sanita, M. E., Dastpak, M., O’Connell, J. D., Coady, J. A., Zhang, J., Gygi, S. P., Lopez-Gonzalez, R., Yin, S., & Reed, R. (2023). Causal ALS genes impact the MHC class II antigen presentation pathway. Proceedings of the National Academy of Sciences of the United States of America, 120(39), Article e2305756120. https://doi.org/10.1073/pnas.2305756120

Chi, B, Öztürk, MM, Paraggio, CL, Leonard, CE, Sanita, ME, Dastpak, M, O’Connell, JD, Coady, JA, Zhang, J, Gygi, SP, Lopez-Gonzalez, R, Yin, S & Reed, R 2023, 'Causal ALS genes impact the MHC class II antigen presentation pathway', Proceedings of the National Academy of Sciences of the United States of America, vol. 120, no. 39, e2305756120. https://doi.org/10.1073/pnas.2305756120

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title = "Causal ALS genes impact the MHC class II antigen presentation pathway",

abstract = "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 FUSR495X 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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author = "Binkai Chi and {\"O}zt{\"u}rk, {Muhammet M.} and Paraggio, {Christina L.} and Leonard, {Claudia E.} and Sanita, {Maria E.} and Mahtab Dastpak and O{\textquoteright}Connell, {Jeremy D.} and Coady, {Jordan A.} and Jiuchun Zhang and Gygi, {Steven P.} and Rodrigo Lopez-Gonzalez and Shanye Yin and Robin Reed",

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AU - Öztürk, Muhammet M.

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AU - Sanita, Maria E.

AU - Dastpak, Mahtab

AU - O’Connell, Jeremy D.

AU - Coady, Jordan A.

AU - Zhang, Jiuchun

AU - Gygi, Steven P.

AU - Lopez-Gonzalez, Rodrigo

AU - Yin, Shanye

AU - Reed, Robin

PY - 2023

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N2 - 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 FUSR495X 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.

AB - 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 FUSR495X 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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Causal ALS genes impact the MHC class II antigen presentation pathway

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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