Glial Cell Dysfunction in C9orf72-Related Amyotrophic Lateral Sclerosis and Frontotemporal Dementia

Abstract

Since the discovery of the chromosome 9 open reading frame 72 (C9orf72) repeat expansion mutation in 2011 as the most common genetic abnormality in amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig's disease) and frontotemporal dementia (FTD), progress in understanding the signaling pathways related to this mutation can only be described as intriguing. Two major theories have been suggested-(i) loss of function or haploinsufficiency and (ii) toxic gain of function from either C9orf72 repeat RNA or dipeptide repeat proteins (DPRs) generated from repeat-associated non-ATG (RAN) translation. Each theory has provided various signaling pathways that potentially participate in the disease progression. Dysregulation of the immune system, particularly glial cell dysfunction (mainly microglia and astrocytes), is demonstrated to play a pivotal role in both loss and gain of function theories of C9orf72 pathogenesis. In this review, we discuss the pathogenic roles of glial cells in C9orf72 ALS/FTD as evidenced by pre-clinical and clinical studies showing the presence of gliosis in C9orf72 ALS/FTD, pathologic hallmarks in glial cells, including TAR DNA-binding protein 43 (TDP-43) and p62 aggregates, and toxicity of C9orf72 glial cells. A better understanding of these pathways can provide new insights into the development of therapies targeting glial cell abnormalities in C9orf72 ALS/FTD.

Keywords: C9orf72 gene; C9orf72 repeat expansion mutation; amyotrophic lateral sclerosis (ALS); astrocytes; frontotemporal dementia (FTD); glial cells; microglia.

Figure 1

Clinical findings at onset in the chromosome 9 open reading frame 72 (C9orf72)-associated amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD).

Figure 2

DNA sequence, three transcription variants, and two protein isoforms of C9orf72. The 11-exon-containing C9orf72 gene undergoes alternative splicing, producing three transcript variants. The (G₄C₂)_n repeat expansion mutation (dark red region) is located in intron 1 of variants 1 and 3, whereas in variant 2, it is located within the promoter region. Coding exons are represented in orange and non-coding exons in blue (not to scale).

Figure 3

Pathogenic mechanisms implicated in C9orf72 ALS/FTD. Both loss and gain of function mechanisms contribute to the disease process in C9orf72 ALS/FTD. Abbreviations: ADA, adenosine deaminase; C1qb, complement component 1, Q subcomponent, β polypeptide; C3ar1, complement component 3a receptor 1; DENN, differentially expressed in normal and neoplastic cells; EAAT, excitatory amino-acid transporter; GEF, GEF, guanine nucleotide exchange factor; GluN1 R, glutamate ionotropic receptor NMDA type subunit 1; GluR1, glutamate ionotropic receptor AMPA type subunit 1; GS, glutamine synthetase; LCD, low complexity domain; LLPS, liquid–liquid phase separation; miRNA, microRNA; PC, pyruvate carboxylase; rRNA, ribosomal RNA; TREM2, triggering receptor expressed on myeloid Cells 2; TYROBP, tyrosine kinase binding protein; and VGCC, voltage-gated calcium channel.

Figure 4

Pathogenic mechanisms underlying glial cell toxicity in neurodegeneration. Microglia and astrocytes become overactivated and lead to neurotoxicity through several mechanisms. Activated microglia and astrocytes produce excess noxious pro-inflammatory factors, such as nitric oxide (NO), reactive oxygen species (ROS, e.g., H₂O₂ and ONOO⁻), several cytokines (e.g., interleukin [IL]-1β, IL-6, and tumor necrosis factor [TNF]-α), and glutamate. AMPAR, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor; GR, glutamate receptor; MHC, major histocompatibility complex; and NMDAR, N-methyl-D-aspartate (NMDA) receptor.