Abstract
The DNA/RNA-binding proteins TDP-43 and FUS are found in protein aggregates in a growing number of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and related dementia, but little is known about the neurotoxic mechanisms. We have generated Caenorhabditis elegans and zebrafish animal models expressing mutant human TDP-43 (A315T or G348C) or FUS (S57Δ or R521H) that reflect certain aspects of ALS including motor neuron degeneration, axonal deficits, and progressive paralysis. To explore the potential of our humanized transgenic C. elegans and zebrafish in identifying chemical suppressors of mutant TDP-43 and FUS neuronal toxicity, we tested three compounds with potential neuroprotective properties: lithium chloride, methylene blue and riluzole. We identified methylene blue as a potent suppressor of TDP-43 and FUS toxicity in both our models. Our results indicate that methylene blue can rescue toxic phenotypes associated with mutant TDP-43 and FUS including neuronal dysfunction and oxidative stress.
Highlights
amyotrophic lateral sclerosis (ALS) is a late-onset progressive neurodegenerative disease affecting motor neurons and resulting in fatal paralysis [1,2]
With this assay we tested if lithium chloride, methylene blue (MB) or riluzole could suppress the paralysis caused by mTDP-43 and mFUS (Figure 1)
Of the three compounds tested, we observed that MB reduced the rate of paralysis for mTDP-43 and mFUS transgenics with no effect on wild type TDP-43 or wild type FUS control strains (Figures 1B, 1E)
Summary
ALS is a late-onset progressive neurodegenerative disease affecting motor neurons and resulting in fatal paralysis [1,2]. A recent biochemical approach identified cytosolic aggregates of TDP-43 in ALS and frontotemporal lobar dementia pathological tissue [3]. This breakthrough discovery was quickly followed by the identification of TDP-43 mutations in ALS patients by numerous groups [3,4,5,6]. FUS inclusions have been observed in clinically distinct forms of frontotemporal lobar dementia and the polyglutamine diseases [8] suggesting that TDP-43 and FUS may be a common pathogenic factor in neurodegeneration. In the absence of knowledge concerning the biochemical defects caused by these ALS-related mutations in TDP-43 and FUS, the use of in vivo models is currently the most promising approach available to further our understanding of pathogenic mechanisms as well as for therapeutic discovery for ALS
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