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

Abstract

Intronic G 4 C 2 hexanucleotide repeat expansions (HRE) of C9orf72 are the most common cause of familial variants of frontotemporal dementia/amyotrophic lateral sclerosis (FTD/ALS). G 4 C 2 HREs in C9orf72 undergo non-canonical repeat-associated translation, producing dipeptide repeat (DPR) proteins, with various deleterious impacts on cellular homeostasis. While ve 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 de cits, neurodegeneration, and neuroin ammation. Neuroin ammation 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) in ammasome in the pathogenesis of FTD/ALS. We nd that in ammasome-mediated neuroin ammation 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 nd that genetic ablation of Nlrp3 signi cantly improved survival, protected behavioral de cits and prevented neurodegeneration suggesting a novel mechanism involving HRE-mediated induction of innate immunity. The ndings provide experimental evidence of the integral role of HRE in in ammasome-mediated innate immunity in the C9orf72 variant of FTD/ALS pathogenesis and suggest the NLRP3 in ammasome as a therapeutic target.

Moderate intrinsic phenotypic alterations in C9orf72 ALS/FTD iPSC-microglia despite the presence of C9orf72 pathological features

“…Here, C9orf72 ALS/FTD iPSC-MG mono-cultures exhibit a comparable response to control iPSC-MG upon LPS stimulation. Further studies are necessary to determine if C9orf72 ALS/FTD iPSC-MG present or exacerbate an inflammatory phenotype when stimulated to induce more specific inflammatory responses, such as activation of the inflammasome via the NLRP pathway (Fu et al, 2022 ; Trageser et al, 2023 ) or co-stimulation of LPS and IFNγ to specifically activate pro-inflammatory pathways (Kann et al, 2022 ). Furthermore, it will be interesting to examine inflammatory responses when iPSC-MG are co-cultured with diseased neurons or astrocytes knowing that direct contact of iPSC-MG with CNS cells can influence their gene expression (Abud et al, 2017 ).…”

Spatiotemporal proteomic profiling of cellular responses to NLRP3 agonists

“…Notably, both treatments caused reduced lysosomal localization of the C9orf72 complex (C9orf72, SMCR8, and WDR41), which localizes to lysosomes and the cytoplasm [90][91]. Mutations in this complex lead to familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) [92], and recent studies demonstrated that genetic ablation of the C9orf72 complex caused sustained NLRP3 inflammasome activation in microglia [93][94]. Previous lysosomal proteomics of damaged lysosomes, induced by either LLoMe or GPN [95][96], only identified one protein of this complex [88][97].…”

Glycine-Alanine Dipeptide Repeat Protein from C9-ALS Interacts with Sulfide Quinone Oxidoreductase (SQOR) to Induce the Activity of the NLRP3 Inflammasome in HMC3 Microglia: Irisflorentin Reverses This Interaction

“…Microglia are the most important immune cells in the brain and play an important role in maintaining the health of neurons and homeostasis of niches [44]. Activation of the NLRP3 inflammasome in microglia is known to be an important pathological factor in ALS [45]. Priming and activation are two essential steps for activating the canonical NLRP3 inflammasome [46].…”