Causal ALS genes impact the MHC class II antigen presentation pathway

Proc Natl Acad Sci U S A. 2023 Sep 26;120(39):e2305756120. doi: 10.1073/pnas.2305756120. Epub 2023 Sep 18.


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.

Keywords: ALS; C9ORF72; FUS; MHC II.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyotrophic Lateral Sclerosis* / genetics
  • Antigen Presentation / genetics
  • Genes, MHC Class II
  • Humans
  • Major Histocompatibility Complex
  • Motor Neurons
  • Nuclear Matrix-Associated Proteins
  • RNA-Binding Proteins / genetics


  • MATR3 protein, human
  • RNA-Binding Proteins
  • Nuclear Matrix-Associated Proteins