Inflammasome mediated neuronal-microglial crosstalk: a therapeutic substrate for the familialC9orf72variant of the frontotemporal dementia/amyotrophic lateral sclerosis

Abstract

Intronic G4C2 hexanucleotide repeat expansions of C9orf72 are the most common cause of familial variants of frontotemporal dementia / amyotrophic lateral sclerosis (FTD/ALS)1,2. G4C2 hexanucleotide repeat expansions (HREs) in C9orf72 undergo non-canonical repeat associated translation, producing dipeptide repeat (DPR) proteins, with various deleterious impacts on cellular homeostasis 3. 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 4,5. Previous work has demonstrated the profound effects of a poly(GR) model of c9FTD/ALS, including motor impairment, memory deficits, neurodegeneration, and neuroinflammation6. Neuroinflammation is hypothesized to be a driving factor in the disease course; microglia activation is present prior to symptom onset and persists throughout the disease7. Here, we establish the contributions of the NLRP3 inflammasome in the pathogenesis of FTD/ALS, resulting from a stress-induced neuronal-microglial crosstalk feedforward loop. In a mouse model of c9FTD/ALS, inflammasome-mediated inflammation was increased with microglial activation, cleavage of caspase-1, upregulation of Cxcl10, and production of IL-1β. We find that genetic ablation of Nlrp3 protected behavioral deficits and prevented neurodegeneration as seen in C57BL6J Wild Type mouse model of c9FTD/ALS. Ultimately, survival was improved by the genetic ablation of Nlrp3. Moreover, we identified the process by which neuronal stress signals induced by hexanucleotide expansions initiate an inflammatory cascade in microglia. These findings provide evidence of the integral role of inflammasome-mediated innate immunity in c9FTD/ALS pathogenesis, and suggest the NLRP3 inflammasome as a therapeutic target.