Therapeutic modulation of eIF2α phosphorylation rescues TDP-43 toxicity in amyotrophic lateral sclerosis disease models

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal, late-onset neurodegenerative disease primarily impacting motor neurons. A unifying feature of many proteins associated with ALS, including TDP-43 and Ataxin-2, is that they localize to stress granules. Unexpectedly, we found that genes that modulate stress granules are striking modifiers of TDP-43 toxicity in Saccharomyces cerevisiae and Drosophila melanogaster, eIF2α phosphorylation is upregulated by TDP-43 toxicity in flies, and TDP-43 interacts with a central stress granule component polyA binding protein (PABP). In human ALS spinal cord neurons, PABP accumulates abnormally, suggesting that prolonged stress granule dysfunction may contribute to pathogenesis. We investigated the efficacy of a small molecule inhibitor of eIF2α-phosphorylation in ALS models. This treatment mitigated TDP-43 toxicity in flies and mammalian neurons. These findings indicate that dysfunction induced by prolonged stress granule formation may contribute directly to ALS and that compounds that mitigate this process may represent a novel therapeutic approach.

mRNP granules

“…136 Supporting these ideas, ALS pathology is suppressed in model systems and patients where autophagy is upregulated, 145,146 or when stress granule assembly is impaired. 147 In addition, pathogenic forms of TDP-43 expressed in C. elegans or Drosophila show slower exchange rates from aggregates or neuronal granules by FRAP. 127,148 Several reasons have been proposed as to why persistent stress granules or related mRNP aggregates could be toxic to cells.…”

Clioquinol promotes the degradation of metal-dependent amyloid-β (Aβ) oligomers to restore endocytosis and ameliorate Aβ toxicity

“…The Aβ, α-synuclein (i.e., Parkinson disease), TDP-43 (i.e., frontotemporal dementia and ALS), and htt72Q (i.e., Huntington disease) yeast models have comparable levels of toxicity, but in each case the nature of the cellular toxicity is distinct as are the genetic hits obtained from unbiased genome-wide modifier screens (8,(21)(22)(23). CQ had significant, yet modest efficacy against α-syn and htt72Q and no effect on TDP-43 (Fig.…”

Linking RNA Dysfunction and Neurodegeneration in Amyotrophic Lateral Sclerosis

“…In support of this hypothesis, genes that regulate the formation of stress granules also modulate TDP43-mediated toxicity in yeast, flies, and primary rodent neurons [99,100]. Deletion of the RNA-binding domains in TDP43 and FUS both prevents their inclusion in stress granules and reduces their toxicity [34,[39][40][41].…”

“…Deletion of the RNA-binding domains in TDP43 and FUS both prevents their inclusion in stress granules and reduces their toxicity [34,[39][40][41]. Moreover, components of stress granules have been detected in TDP43-rich cytoplasmic deposits in spinal neurons of patients with ALS [56,99,101], but are less common in cortical neurons [102]. These results may be explained by the preferential accumulation of fulllength TDP43 in spinal neurons of patients with ALS, in contrast to the deposition of carboxy-terminal fragments of TDP43 in cortical neurons [103].…”