Curcumin abolishes mutant TDP-43 induced excitability in a motoneuron-like cellular model of ALS

H. Dong, L. Xu, L. Wu, X. Wang, W. Duan, H. Li, C. Li

Research output: Contribution to journalArticlepeer-review

24 Citations (Scopus)

Abstract

Mutation of TAR DNA-binding protein-43 (TDP-43) is detected in familial and sporadic amyotrophic lateral sclerosis (FALS and SALS). TDP-43-positive cytoplasmic inclusions are present in both neuron and glia of ALS, although not in mutant Cu/Zn-superoxide dismutase (mSOD1)-related or RNA binding protein Fused in sarcoma (FUS)-related ALS. Previous studies have established that cortical hyper-excitability is common to both FALS and SALS patients. Much of our current understanding of neuron excitability has come from studying the subtype of mSOD1-related ALS. Thus, we evaluated the excitable capability through analyzing properties of action potentials (APs) and voltage-gated sodium (Na v ) channels on the cellular model, motoneuron-like cell lines that were steadily transfected with mutant Q331K and wild-type TDP-43. We found that wild-type TDP-43 increased firing frequency of APs, but the presence of mutant Q331K TDP-43 enhanced firing frequency and decreased the threshold of APs to a higher level. Further, we observed that mutant Q331K and wild-type TDP-43 induced more rapid speed of recovery from fast and slow inactivation of Na v channels and resulted in a reduction of voltage dependency of slow inactivation. These results provide evidence for high excitability that resulted from the presence of mutant and wild-type TDP-43, and more toxicity of mutant TDP-43 than wild-type. Other studies suggest that Na v channel activity can be increased directly by different oxidative species and, we have shown previously that oxidative stress and mitochondrial dysfunction occurs simultaneously in the cellular model of mutant TDP-43 and can be ameliorated by dimethoxy curcumin (DMC), a safe and effective antioxidant. In the present study we found that the abnormities of APs and Na v channels were significantly ameliorated when treated with DMC (15μM) for 24h, suggesting a dropping-excitability state. Taken together, mutant Q331K TDP-43 induces high excitability in a motoneuron-like cellular model, and this abnormal state is rescued by DMC which may act through alleviation of oxidative stress and mitochondrial dysfunction.

Original languageEnglish
Pages (from-to)141-153
Number of pages13
JournalNeuroscience
Volume272
DOIs
Publication statusPublished - Jul 11 2014
Externally publishedYes

Keywords

  • Action potential
  • Amyotrophic lateral sclerosis
  • Dimethoxy curcumin
  • Excitability
  • TDP-43
  • Voltage-gated sodium channel

ASJC Scopus subject areas

  • Neuroscience(all)

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