Divergence, Convergence, and Therapeutic Implications: A Cell Biology Perspective of C9ORF72-ALS/FTD

Abstract

Ever since a GGGGCC hexanucleotide repeat expansion mutation in C9ORF72 was identified as the most common cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), three competing but nonexclusive hypotheses to explain how this mutation causes diseases have been proposed and are still under debate. Recent studies in the field have tried to understand how the repeat expansion disrupts cellular physiology, which has suggested interesting convergence of these hypotheses on downstream, functional defects in cells, such as nucleocytoplasmic transport disruption, membrane-less organelle defects, and DNA damage. These studies have not only provided an integrated view of the disease mechanism but also revealed novel cell biology implicated in neurodegeneration. Furthermore, some of the discoveries have given rise to new ideas for therapeutic development. Here, we review the research progress on cellular pathophysiology of C9ORF72-mediated ALS and FTD and its therapeutic implication. We suggest that the repeat expansion drives pathogenesis through a combination of downstream defects, of which some can be therapeutic targets.

Keywords: Amyotrophic lateral sclerosis; C9orf72; Frontotemporal dementia.

Fig. 1

Summary of current cellular pathophysiological studies on C9ALS/FTD. a Three hypothesized primary assaults caused by the C9ORF72 mutation: 1) loss of C9ORF72 function, 2) repeat RNA forming either G-quartets or R-loops, toxic secondary structures that either sequester RBPs or cause DNA damage, respectively, and 3) DPRs. b The three primary assaults cause downstream, functional defects in nerve cells, and a combination of these defects causes neurodegeneration. c Therapeutic approaches can target either the primary assaults themselves, or their downstream effectors.

Fig. 2

Connections among functional defects downstream of repeat RNAs and DPRs. a G-quartets formed by repeat RNAs disrupt nucleocytoplasmic transport by sequestering RanGAP. It also promotes stress granule assembly. b DPRs induce stress granule assembly, which disrupts nucleocytoplasmic transport, inhibits global translation, and enhances RAN translation. Enhanced RAN translation produces more DPRs, forming a feedforward loop. c G-quartets formed by repeat RNAs disrupt nucleoli by sequestering NCL, whereas DPRs disrupt nucleoli by co-phase separating with NPM1 and NCL. In addition, DPRs cause DNA damage via NPM1 and nucleolar defects. d Repeat RNAs form R-loops, which causes DNA damage. e Cytoplasmic DPRs disrupt mitochondrial function, producing ROS that causes DNA damage. These discoveries not only provide us with an integrated view of C9ALS/FTD pathogenic mechanism but also help us better understand the fundamental biology underlying neurodegeneration.