Respiration Enhances TDP-43 Toxicity, but TDP-43 Retains Some Toxicity in the Absence of Respiration

JOURNAL OF MOLECULAR BIOLOGY

卷:431

Article

Park, Sei-Kyoung¹  Park, Sangeun¹  Liebman, Susan W.¹ 

[1] Univ Nevada, Dept Pharmacol, Reno, NV 89557 USA

关键词: TDP-43;    amyotrophic lateral sclerosis;    yeast;    respiration;    mitochondria;   

DOI  :  10.1016/j.jmb.2019.03.014

来源: Elsevier

【 摘 要 】

The trans-activating response DNA-binding protein 43 (TDP-43) is a transcriptional repressor and splicing factor. TDP-43 is normally mostly in the nucleus, although it shuttles to the cytoplasm. Mutations in TDP-43 are one cause of familial amyotrophic lateral sclerosis. In neurons of these patients, TDP-43 forms cytoplasmic aggregates. In addition, wild-type TDP-43 is also frequently found in neuronal cytoplasmic aggregates in patients with neurodegenerative diseases not caused by TDP-43 mutations. TDP-43 expressed in yeast causes toxicity and forms cytoplasmic aggregates. This disease model has been validated because genetic modifiers of TDP-43 toxicity in yeast have led to the discovery that their conserved genes in humans are amyotrophic lateral sclerosis genetic risk factors. While how TDP-43 is associated with toxicity is unknown, several studies find that TDP-43 alters mitochondrial function. We now report that TDP-43 is much more toxic when yeast are respiring than when grown on a carbon source where respiration is inhibited. However, respiration is not the unique target of TDP-43 toxicity because we found that TDP-43 retains some toxicity even in the absence of respiration. We found that H2O2 increases the toxicity of TDP-43, suggesting that the reactive oxygen species associated with respiration could likewise enhance the toxicity of TDP-43. In this case, the TDP-43 toxicity targets in the presence or absence of respiration could be identical, with the reactive oxygen species produced by respiration activating TDP-43 to become more toxic or making TDP-43 targets more vulnerable. (C) 2019 Elsevier Ltd. All rights reserved.

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