Mechanisms of Immune Activation by c9orf72-Expansions in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia

Abstract

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative disorders with overlapping pathomechanisms, neurobehavioral features, and genetic etiologies. Individuals diagnosed with either disorder exhibit symptoms within a clinical spectrum. Symptoms of ALS involve neuromusculature deficits, reflecting upper and lower motor neurodegeneration, while the primary clinical features of FTD are behavioral and cognitive impairments, reflecting frontotemporal lobar degeneration. An intronic G 4 C 2 hexanucleotide repeat expansion (HRE) within the promoter region of chromosome 9 open reading frame 72 (C9orf72) is the predominant monogenic cause of both ALS and FTD. While the heightened risk to develop ALS/FTD in response to C9orf72 expansions is well-established, studies continue to define the precise mechanisms by which this mutation elicits neurodegeneration. Studies show that G 4 C 2 expansions undergo repeat-associated non-ATG dependent (RAN) translation, producing dipeptide repeat proteins (DRPs) with varying toxicities. Accumulation of DRPs in neurons, in particular arginine containing DRPs, have neurotoxic effects by potently impairing nucleocytoplasmic transport, nucleotide metabolism, lysosomal processes, and cellular metabolic pathways. How these pathophysiological effects of C9orf72 expansions engage and elicit immune activity with additional neurobiological consequences is an important line of future investigations. Immunoreactive microglia and elevated levels of peripheral inflammatory cytokines noted in individuals with C9orf72 ALS/FTD provide evidence that persistent immune activation has a causative role in the progression of each disorder. This review highlights the current understanding of the cellular, proteomic and genetic substrates through which G 4 C 2 HREs may elicit detrimental immune activity, facilitating region-specific neurodegeneration in C9orf72 mediated ALS/FTD. We in particular emphasize interactions between intracellular pathways induced by C9orf72 expansions and innate immune inflammasome complexes, intracellular receptors responsible for eliciting inflammation in response to cellular

Longitudinal biomarkers in amyotrophic lateral sclerosis

“…Recent research in C9orf72 ALS individuals and preclinical animal models with human C9orf72 mutations increasingly suggests a potential role for autoimmunity. 33,34 Indeed, TNF-a seems to be specifically higher in the C9orf72 group in both CSF and plasma. Elevations in inflammatory cytokines and sTREM2, markers of activated microglial cells and macrophages in fast progressors and C9orf72 ALS patients, suggests activation of glial cells and peripheral immune cells at variable magnitudes depending on the disease progression rate.…”

“…Indeed, in our cohort, all but one of the C9orf72 patients were fast progressors, so it remains unclear if the elevated cytokines in this group are due to the effects of the specific genotype or simply reflect the faster disease progression. Recent research in C9orf72 ALS individuals and preclinical animal models with human C9orf72 mutations increasingly suggests a potential role for autoimmunity 33,34 . Indeed, TNF‐α seems to be specifically higher in the C9orf72 group in both CSF and plasma.…”

TDP-43 and Inflammation: Implications for Amyotrophic Lateral Sclerosis and Frontotemporal Dementia

“…However, this was not unique to TDP-43 given aggravated and soluble SOD1 G93A also activates NLRP3 in primary mouse microglia. Of particular interest to ALS and FTD, NLRP3 inflammatory activation can be generated by C90rf72 repeat expansions, leading to lysosomal dysfunction, mitochondrial functional impairments, intracellular metabolic imbalances, and intracellular protein aggregation [137].…”

Aberrant NLRP3 Inflammasome Activation Ignites the Fire of Inflammation in Neuromuscular Diseases

“…In this context, exposure of cultured murine and human macrophages to monomeric TDP-43—but not its fibrillary form—was shown to activate the NLRP3 inflammasome and release IL-1β. In addition, C9ORF72-derived glycine–arginine (GR) dipeptide repeats were also phagocytosed by macrophages, stimulated NLRP3 and released IL-1β [ 185 ]. This study suggests that ALS-associated proteins can drive inflammatory processes.…”