Curcumin abolishes mutant TDP-43 induced excitability in a motoneuron-like cellular model of ALS.
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 (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.
Department of Neurology, The Second Hospital of Hebei Medical University, 215 Heping West Road, Shijiazhuang, Hebei 050000, China; Institute of Cardiocerebrovascular Disease, 215 Heping West Road, Shijiazhuang, Hebei 050000, China; Neurological Laboratory of Hebei Province, 215 Heping West Road, Shijiazhuang, Hebei 050000, China.
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Dong
Department of Neurology, The Second Hospital of Hebei Medical University, 215 Heping West Road, Shijiazhuang, Hebei 050000, China; Institute of Cardiocerebrovascular Disease, 215 Heping West Road, Shijiazhuang, Hebei 050000, China; Neurological Laboratory of Hebei Province, 215 Heping West Road, Shijiazhuang, Hebei 050000, China.
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Xu
Department of Neurology, The Second Hospital of Hebei Medical University, 215 Heping West Road, Shijiazhuang, Hebei 050000, China.
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Wu
Department of Neurology, The Second Hospital of Hebei Medical University, 215 Heping West Road, Shijiazhuang, Hebei 050000, China.
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Wang
Department of Neurology, The Second Hospital of Hebei Medical University, 215 Heping West Road, Shijiazhuang, Hebei 050000, China; Institute of Cardiocerebrovascular Disease, 215 Heping West Road, Shijiazhuang, Hebei 050000, China; Neurological Laboratory of Hebei Province, 215 Heping West Road, Shijiazhuang, Hebei 050000, China.
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Duan
Department of Neurology, The Second Hospital of Hebei Medical University, 215 Heping West Road, Shijiazhuang, Hebei 050000, China.
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Li
Department of Neurology, The Second Hospital of Hebei Medical University, 215 Heping West Road, Shijiazhuang, Hebei 050000, China; Institute of Cardiocerebrovascular Disease, 215 Heping West Road, Shijiazhuang, Hebei 050000, China; Neurological Laboratory of Hebei Province, 215 Heping West Road, Shijiazhuang, Hebei 050000, China. Electronic address: hblicy5@aliyun.com.
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Li
D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism*; D001921:Brain / Q000378:metabolism*; D003474:Curcumin / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D002479:Inclusion Bodies; D009046:Motor Neurons / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D009457:Neuroglia / Q000378:metabolism; D013116:Spinal Cord / Q000378:metabolism
D004268:DNA-Binding Proteins; D003474:Curcumin
TDP-43; action potential; amyotrophic lateral sclerosis; dimethoxy curcumin; excitability; voltage-gated sodium channel