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 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.

Linking ALS mutations to the disruption of the MHC-II pathway

“…However, the direct connection between genetic causes and the impaired immune system was still elusive. In this issue of PNAS, Chi et al reported that several ALS-associated RNA/DNA-binding proteins and C9ORF72 repeat expansion influence the gene expression of components in the major histocompatibility complex II (MHC-II) antigen presentation pathway ( 4 ). This possibly leads to immune system dysfunction which can contribute to neurodegeneration in ALS.…”

“…Many studies focused on their functions in neurons ( 18 ), although these proteins are expressed broadly in many cell types, including immune cells. In this work, Chi et al found that many immune-related proteins were down-regulated after knocking out FUS, TAF15, or MATR3 in HeLa cells using quantitative mass spectrometry analysis ( 4 ). Among the down-regulated genes affected by all the three RNA/DNA-binding proteins, a significant portion has functions related to antigen presentation.…”