Causal ALS genes impact the MHC class II antigen presentation pathway.

Area of Science:

• Neuroscience
• Immunology
• Genetics

Background:

• Amyotrophic lateral sclerosis (ALS) is linked to mutations in RNA/DNA-binding proteins.
• The precise mechanisms driving ALS pathogenesis remain largely unknown.
• The role of immune pathways in ALS is an area of active investigation.

Purpose of the Study:

• To investigate the impact of ALS-associated proteins on the major histocompatibility complex II (MHC II) pathway.
• To determine if disruptions in MHC II expression are present in cellular models of ALS.
• To explore the potential immunological consequences of these disruptions in ALS.

Main Methods:

• Utilized gene knockouts and knockdowns of ALS-associated proteins (FUS, EWSR1, TAF15, MATR3) in HeLa and human microglial cells.
• Assessed the expression levels of MHC II components, including HLA-DR and the transcription factor CIITA.
• Examined MHC II expression in hematopoietic progenitor cells (HPCs) derived from patient-specific induced pluripotent stem cells (FUS^R495X and C9ORF72 mutations).

Main Results:

• Down-regulation of both HLA-DR subunits was observed in cells with knocked-out/knocked-down ALS genes.
• Loss of the MHC II transcription factor CIITA was identified as the cause of decreased MHC II expression.
• Disrupted MHC II expression was confirmed in HPCs derived from FUS^R495X and C9ORF72 ALS patient iPSCs.

Conclusions:

• ALS-associated proteins play a critical role in regulating the MHC II antigen presentation pathway.
• Impaired MHC II expression in HPCs suggests a potential global immune system failure in ALS.
• This immune dysfunction may compromise motor neuron protection, contributing to ALS development and progression.