C9ORF72 suppresses JAK-STAT mediated inflammation

Area of Science:

• Neuroscience
• Immunology
• Genetics

Background:

• Hexanucleotide repeat expansion in C9ORF72 is a primary genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD).
• C9ORF72 deficiency in mice results in significant inflammatory responses, but the precise regulatory mechanisms are not fully understood.

Purpose of the Study:

• To elucidate the mechanism by which C9ORF72 deficiency leads to inflammation.
• To investigate the role of the JAK-STAT pathway and STING in C9ORF72-related inflammation.
• To explore potential therapeutic strategies targeting the JAK-STAT pathway for ALS/FTLD.

Main Methods:

• Investigated the effects of C9ORF72 loss on the JAK-STAT pathway and STING protein levels in cell culture and mouse models.
• Utilized JAK inhibitors to assess their efficacy in mitigating inflammatory phenotypes.
• Examined lysosome integrity in the context of C9ORF72 deficiency.

Main Results:

• Loss of C9ORF72 leads to hyperactivation of the JAK-STAT pathway.
• C9ORF72 deficiency increases STING protein levels, a key mediator of DNA-sensing immune responses.
• JAK inhibitor treatment effectively reversed the inflammatory phenotypes associated with C9ORF72 deficiency.
• Ablation of C9ORF72 compromises lysosome integrity, potentially contributing to inflammatory signaling.

Conclusions:

• C9ORF72 regulates inflammation through the JAK-STAT pathway and STING signaling.
• Compromised lysosome integrity in C9ORF72-deficient cells may drive inflammatory responses.
• Targeting the JAK-STAT pathway offers a promising therapeutic avenue for ALS/FTLD patients with C9ORF72 mutations.