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 G₄C₂ 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 G₄C₂ 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 G₄C₂ 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 stress. A further understanding of the intricate, reciprocal relationship between the cellular and molecular pathologies resulting from C9orf72 HREs and immune activation may yield novel therapeutics for ALS/FTD, which currently have limited treatment strategies.

Keywords: C9orf72; TDP-43; amyotrophic lateral sclerosis (ALS); frontotemporal dementia (FTD); innate immunity; microglia; reactive oxygen species (ROS); therapeutics.

FIGURE 1

Structural and proteinopathic effects of the C9orf72 hexanucleotide repeat expansion. The C9orf72 HRE consists of an expanded intronic sequence of GGGGCC in the open reading frame 72 of chromosome 9 and produces DRPs in one of three reading frames. DPRs are produced both in the sense (Glycine-Alanine, Glycine-Arginine, Glycine-Proline) and antisense direction (Glycine-Proline, Proline-Arginine, Proline-Alanine) (A). These DPRs have varying degrees of toxicity within the cell, with the arginine containing DPR the most pathogenic (B). The HRE forms a G-quadruplex structure due to hydrogen bonding between guanine bases (blue), and DNA–RNA R Loops form. RNA polymerase is unable to continuously transcribe mRNA, causing the accumulation of abortive transcripts (C).

FIGURE 2

Mechanism of immune activation by byproducts of the C9orf72 repeat expansion. C9orf72 pathology is driven by the presence of an expanded HRE, producing various cellular pathologies. DRPs are produced via RAN translation and subsequently accumulate, causing cellular stress. In response, the cell forms SGs which are unable to readily dissolve. TDP-43 is subsequently recruited to these SGs, and there is upregulation of eIF2α phosphorylation thereby increasing the efficiency of RAN translation, thereby perpetuating the cycle. Microglia sense neuronal stress and in response release various cytokines and ROS. ROS increase the efficiency of RAN translation, furthering the feedback loop of pathology and neurodegeneration.