Inflammasome mediated neuronal-microglial crosstalk: a therapeutic substrate in C9orf72-FTD/ALS.

Trageser, K. J.; Smith, C.; Sebastian-Valverde, M.; Iqbal, U. H.; Wu, H.; Estill, M.; Al Rahim, M.; Raval, U.; Herman, F. J.; Zeng, E.; Iban Arias, R.; Oguchi, T.; Zhang, Y.-J.; Petrucelli, L.; Pasinetti, G. M.

doi:10.1101/2022.01.27.478078

bioRxiv · 10.1101/2022.01.27.478078

Inflammasome mediated neuronal-microglial crosstalk: a therapeutic substrate in C9orf72-FTD/ALS.

Trageser, K. J.·Smith, C.·Sebastian-Valverde, M.·Iqbal, U. H.·Wu, H.·Estill, M.·Al Rahim, M.·Raval, U.·Herman, F. J.·Zeng, E.·Iban Arias, R.·Oguchi, T.·Zhang, Y.-J.·Petrucelli, L.·Pasinetti, G. M.

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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-1{beta} 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.

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Trageser, K. J., Smith, C., Sebastian-Valverde, M., Iqbal, U. H., Wu, H., Estill, M., Al Rahim, M., Raval, U., Herman, F. J., Zeng, E., Iban Arias, R., Oguchi, T., Zhang, Y.-J., Petrucelli, L., Pasinetti, G. M.. 2022-01-28. Inflammasome mediated neuronal-microglial crosstalk: a therapeutic substrate in C9orf72-FTD/ALS.. https://doi.org/10.1101/2022.01.27.478078

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