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

• Wild-type TDP-43 only increases firing frequency of action potentials.
• Mutant Q331K TDP-43 induces not only higher firing frequency, but also lower threshold of action potentials.
• Mutant Q331K and wild-type TDP-43 lead to increased recovery from fast and slow inactivation of voltage-gated Na+ channels.
• The presence of TDP-43 induces high excitability and the mutant protein is more toxic than wild-type TDP-43.
• Dimethoxy curcumin abolishes the abnormity excitability induced by TDP-43.

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 (Nav) 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 Nav 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 Nav 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 Nav channels were significantly ameliorated when treated with DMC (15 μM) for 24 h, 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.

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