Alterations in stress granule dynamics driven by TDP-43 and FUS: a link to pathological inclusions in ALS?

Abstract

Stress granules (SGs) are RNA-containing cytoplasmic foci formed in response to stress exposure. Since their discovery in 1999, over 120 proteins have been described to be localized to these structures (in 154 publications). Most of these components are RNA binding proteins (RBPs) or are involved in RNA metabolism and translation. SGs have been linked to several pathologies including inflammatory diseases, cancer, viral infection, and neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). In ALS and FTD, the majority of cases have no known etiology and exposure to external stress is frequently proposed as a contributor to either disease initiation or the rate of disease progression. Of note, both ALS and FTD are characterized by pathological inclusions, where some well-known SG markers localize with the ALS related proteins TDP-43 and FUS. We propose that TDP-43 and FUS serve as an interface between genetic susceptibility and environmental stress exposure in disease pathogenesis. Here, we will discuss the role of TDP-43 and FUS in SG dynamics and how disease-linked mutations affect this process.

Keywords: FUS; TDP-43; amyotrophic lateral sclerosis; frontotemporal dementia; microtubules; pathological inclusions; stress granules.

FIGURE 1

Cell lines and stress inducing agents used in stress granule studies. Analysis of 154 articles published between 1999 and 2014. Some publications used many cells type and/or many stresses. (A) Stresses involved in stress granule (SG) studies. (B) Cell lines used in SG studies.

FIGURE 2

Stress granule composition. Analysis of 154 publications between 1999 and 2014. (A) Cellular metabolism functions of proteins recruited to SGs. (B) Specific function in mRNA metabolism of proteins recruited to SGs.

FIGURE 3

TDP-43 and FUS protein structures. FUS and TDP-43 have structural similarities with both harboring a Prion-like domain, RNA recognition motif(s), nuclear localization signal, and nuclear export signal. Details regarding the position of domains were derived from UniProt.

FIGURE 4

Down-regulation of TDP-43 and expression of mutant FUS share SG phenotypes. Delayed SG assembly and faster SG disassembly is observed in cells with reduced levels of TDP-43 as well as cells expressing mutant forms of FUS. This phenotype increases cell vulnerability. Cells reduced in TDP-43 levels will present a defect in SG secondary aggregation concomitant with a decrease in SG/PB docking followed by an increase in mRNA degradation after stress (siTDP-43 cells compared to siControl cells). This effect is mediated via G3BP1. Cells expressing mutant forms of FUS form larger SGs with more labile TIA-1 and G3BP1 protein compared to cells transfected with FUS^WT.