Abstract
The primarily nuclear RNA-binding protein FUS (fused in sarcoma) forms pathological cytoplasmic inclusions in a subset of early-onset amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) patients. In response to cellular stress, FUS is recruited to cytoplasmic stress granules, which are hypothesized to act as precursors of pathological inclusions. We monitored the stress-induced nucleocytoplasmic shuttling of endogenous FUS in an exvivo mouse CNS model and human neural networks. We found that hyperosmolar, but not oxidative, stress induced robust cytoplasmic translocation of neuronal FUS, with transient nuclear clearance and loss of function. Surprisingly, this reaction is independent of stress granule formation and the molecular pathways activated by hyperosmolarity. Instead, it represents a mechanism mediated by cytoplasmic redistribution of Transportin 1/2 and is potentiated by transcriptional inhibition. Importantly, astrocytes, which remain unaffected in ALS/FTD-FUS, are spared from this stress reaction that may signify the initial event in the development of FUS pathology.
Highlights
The RNA/DNA-binding protein FUS has been implicated in the pathogenesis of two devastating neurodegenerative diseases, amyotrophic lateral sclerosis (ALS) (Kwiatkowski et al, 2009; Vance et al, 2009) and frontotemporal dementia (FTD) (Neumann et al, 2009)
But Not Oxidative, Stress Drives Cytoplasmic Translocation of Endogenous Neuronal FUS To understand the involvement of cellular stress in the initiation of FUS pathology, we used mouse brain organotypic corticohippocampal slices, which are morphologically similar to the intact CNS (Figure S1A)
In cortical neurons, T-cell intracellular antigen-1 receptor (TIAR)-positive stress granules (SGs) were formed in the cytoplasm, most prominently at 4 hr of osmotic stress (Figure 1A)
Summary
The RNA/DNA-binding protein FUS (fused in sarcoma) has been implicated in the pathogenesis of two devastating neurodegenerative diseases, amyotrophic lateral sclerosis (ALS) (Kwiatkowski et al, 2009; Vance et al, 2009) and frontotemporal dementia (FTD) (Neumann et al, 2009). ALS is characterized by progressive paralysis due to motor neuron degeneration, whereas FTD patients suffer from cognitive impairment, caused by atrophy of the frontal and temporal brain lobes. Despite distinct symptoms, both diseases are clinically, pathologically, and genetically linked, and have possible common underlying causes, involving aberrant localization and aggregation of RNA-binding proteins (Ling et al, 2013). FUS is a ubiquitously expressed ribonucleoprotein (RNP) with several RNA-binding domains that allow its involvement in various steps of RNA metabolism (Lagier-Tourenne et al, 2010). Apart from loss of essential RNA processing functions, pathological mislocalization and aggregation may be toxic because of distorted RNA and protein interactions and mRNP (messenger RNP) dynamics (Bowden and Dormann, 2016)
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