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.

Stress-specific differences in assembly and composition of stress granules and related foci

“…If successful, adaptation to stress is pro-survival, leading to the prediction that defects in SG formation (either no formation or lack of secondary aggregation) may result in decreased cell survival (Aulas and Vande Velde, 2015). Other data suggest that some stresses (such as osmotic stress) can induce 'defective' SGs in cells unable to phosphorylate eIF2α, resulting in apoptosis instead of survival (Bevilacqua et al, 2010).…”

“…The list of SG-promoting stimuli and cell lines that are used for SG studies is extensive and continues to grow (Aulas and Vande Velde, 2015). Most studies presume that SGs are uniformly the same despite differences in stressors or cell type.…”

“…SG proteins not only determine the fate of specific transcripts that shuttle in and out of SGs, but also modulate various signaling cascades in stressed cells. Dysregulation of SG dynamics is implicated in the pathogenesis of a number of human diseases including cancer, inflammatory, neurodegenerative and neuromuscular diseases Kedersha, 2002, 2009;Anderson et al, 2015;Aulas and Vande Velde, 2015;Buchan, 2014;Ivanov and Anderson, 2013;Kedersha et al, 2013;Panas et al, 2016).…”

ALS-Related Mutant FUS Protein Is Mislocalized to Cytoplasm and Is Recruited into Stress Granules of Fibroblasts from Asymptomatic <b><i>FUS </i></b>P525L Mutation Carriers

“…It has been hypothesized that this process, in conditions of persistent stress, might precede the formation of irreversible aggregates in the cytoplasm, the hallmark of ALS with FUS mutations at the 514-526 C-terminal residues [16,22,23]. …”

Neuronal cytoplasmic inclusions in tau, TDP-43, and FUS molecular subtypes of frontotemporal lobar degeneration share similar spatial patterns

“…Fifth, aggregates of phosphorylated TDP-43 (pTDP-43) are frequently present in axons of hypoglossal and facial nerves and in spinal cord anterior cells in MND, consistent with propagation of the protein [44], while FUS activity is found in granules in gray matter of the brain stem and spinal cord, which co-localise with synaptophysin [1], consistent with transport of the protein and synaptic disconnection. Sixth, stress granules are foci of cytoplasmic RNA formed in response to stress and, among many other proteins, also exhibit TDP-43 and FUS immunoreactivity [17]. Hence, the domains involved in the phase separation of liquid droplets such as stress granules may be a precursor to aggregation and propagation of proteins.…”