Inflammasome-Mediated Neuronal-Microglial Crosstalk: a Therapeutic Substrate for the Familial C9orf72 Variant of Frontotemporal Dementia/Amyotrophic Lateral Sclerosis.

Abstract

Intronic G4C2 hexanucleotide repeat expansions (HRE) of C9orf72 are the most common cause of familial variants of frontotemporal dementia/amyotrophic lateral sclerosis (FTD/ALS). G4C2 HREs in C9orf72 undergo non-canonical repeat-associated translation, producing dipeptide repeat (DPR) proteins, with various deleterious impacts on cellular homeostasis. While five different DPRs are produced, poly(glycine-arginine) (GR) is amongst the most toxic and is the only DPR to accumulate in the associated clinically relevant anatomical locations of the brain. Previous work has demonstrated the profound effects of a poly (GR) model of C9orf72 FTD/ALS, including motor impairment, memory deficits, neurodegeneration, and neuroinflammation. Neuroinflammation is hypothesized to be a driving factor in the disease course; microglia activation is present prior to symptom onset and persists throughout the disease. Here, using an established mouse model of C9orf72 FTD/ALS, we investigate the contributions of the nod-like receptor pyrin-containing 3 (NLRP3) inflammasome in the pathogenesis of FTD/ALS. We find that inflammasome-mediated neuroinflammation is increased with microglial activation, cleavage of caspase-1, production of IL-1β, and upregulation of Cxcl10 in the brain of C9orf72 FTD/ALS mice. Excitingly, we find that genetic ablation of Nlrp3 significantly improved survival, protected behavioral deficits, and prevented neurodegeneration suggesting a novel mechanism involving HRE-mediated induction of innate immunity. The findings provide experimental evidence of the integral role of HRE in inflammasome-mediated innate immunity in the C9orf72 variant of FTD/ALS pathogenesis and suggest the NLRP3 inflammasome as a therapeutic target.

• Authors: Kyle J Trageser, Eun-Jeong Yang, Chad Smith, Ruth Iban-Arias, Tatsunori Oguchi, Maria Sebastian-Valverde, Umar Haris Iqbal, Henry Wu, Molly Estill, Md Al Rahim, Urdhva Raval, Francis J Herman, Yong Jie Zhang, Leonard Petrucelli, Giulio Maria Pasinetti
• Journal: Molecular neurobiology (Mol Neurobiol) Vol. 60 Issue 7 Pg. 4004-4016 (Jul 2023) ISSN: 1559-1182 [Electronic] United States
• PMID: 37010807 (Publication Type: Journal Article)
• Copyright: © 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.

Chemical References

• Inflammasomes
• C9orf72 Protein
• NLR Family, Pyrin Domain-Containing 3 Protein
• Dipeptides

Topics

• Animals
• Mice
• Amyotrophic Lateral Sclerosis (metabolism)
• Frontotemporal Dementia (genetics, pathology)
• Microglia (metabolism)
• Inflammasomes
• C9orf72 Protein (genetics)
• NLR Family, Pyrin Domain-Containing 3 Protein (genetics)
• Neuroinflammatory Diseases
• DNA Repeat Expansion (genetics)
• Dipeptides