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. 2023 Jul;60(7):4004-4016.
doi: 10.1007/s12035-023-03315-w. Epub 2023 Apr 3.

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

Kyle J Trageser  1 , Eun-Jeong Yang  1 , Chad Smith  1 , Ruth Iban-Arias  1 , Tatsunori Oguchi  1 , Maria Sebastian-Valverde  1 , Umar Haris Iqbal  1 , Henry Wu  1 , Molly Estill  2 , Md Al Rahim  1 , Urdhva Raval  1 , Francis J Herman  1 , Yong Jie Zhang  3 , Leonard Petrucelli  3 , Giulio Maria Pasinetti  4   5
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Inflammasome-Mediated Neuronal-Microglial Crosstalk: a Therapeutic Substrate for the Familial C9orf72 Variant of Frontotemporal Dementia/Amyotrophic Lateral Sclerosis

Kyle J Trageser et al. Mol Neurobiol. 2023 Jul.

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.

Keywords: Amyotrophic lateral sclerosis; C9orf72; Frontotemporal dementia; Inflammasome; Microglia; Neurodegeneration; Neuroinflammation.

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