TY - JOUR
T1 - Curcumin abolishes mutant TDP-43 induced excitability in a motoneuron-like cellular model of ALS
AU - Dong, H.
AU - Xu, L.
AU - Wu, L.
AU - Wang, X.
AU - Duan, W.
AU - Li, H.
AU - Li, C.
N1 - Funding Information:
We thank the late Dr. Rugao Liu of the University of Louisville, USA for the kind gift of the NSC-34 cell line. We are grateful to Dr.Jemeen Sreedharan and Dr. Christopher E. Shaw at the Department of Clinical Neuroscience, King’s College, London, England for the kind gift of the wild-type and mutant TDP-43 plasmids. This study was supported by grants from National Natural Science Foundation of China and Public Health Department of Hebei Province (Nos. 81171210 and 20110327 ).
PY - 2014/7/11
Y1 - 2014/7/11
N2 - 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.
AB - 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.
KW - Action potential
KW - Amyotrophic lateral sclerosis
KW - Dimethoxy curcumin
KW - Excitability
KW - TDP-43
KW - Voltage-gated sodium channel
UR - http://www.scopus.com/inward/record.url?scp=84901293621&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84901293621&partnerID=8YFLogxK
U2 - 10.1016/j.neuroscience.2014.04.032
DO - 10.1016/j.neuroscience.2014.04.032
M3 - Article
C2 - 24785678
AN - SCOPUS:84901293621
SN - 0306-4522
VL - 272
SP - 141
EP - 153
JO - Neuroscience
JF - Neuroscience
ER -