Neuroprotection by monocarbonyl dimethoxycurcumin C: ameliorating the toxicity of mutant TDP-43 via HO-1.
Mutation of TAR DNA-binding protein-43 (TDP-43) was detected in familiar and sporadic amyotrophic lateral sclerosis, and pathological TDP-43 was identified in the frontotemporal lobar degeneration. The neuroprotective functions of curcumin derivatives were assessed in motor neurons transfected with mutant TDP-43. We found that curcumin derivatives reduced the levels of TDP-43 fragments. Furthermore, we evaluated these compounds on the cellular model that the cells were transfected with TDP-25. We found that the expression level and aggregate formation of TDP-25 were significantly reduced by monocarbonyl dimethoxycurcumin C (Compound C). To study on the neuroprotective functions of curcumin derivatives, the neuroblastoma-spinal cord-34 cells transfected with mutant TDP-43 were assessed by the level of lactate dehydrogenase (LDH) and malondialdehyde bisdimethyl acetal (MDA) that were involved in the oxidative stress. We found that Compound C ameliorated the damage of mutant TDP-43 by reducing the level of MDA and LDH. Furthermore, heme oxygenase-1 (HO-1) was induced by Compound C significantly higher than other compounds. Znpp, which is known an inhibitor of HO-1, dramatically interfered with the function of Compound C. In addition, Compound C was tested in vivo, and HO-1 was significantly upregulated at the hippocampus. These findings suggest that Compound C, which degrades TDP-43 fragment and strengthens the antioxidant ability by HO-1, is a promising agent for TDP-43 proteinopathy.
Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050000, People's Republic of China.
Weisong
W
Duan
Yansu
Y
Guo
Jian
J
Xiao
Xiaoyu
X
Chen
Zhongyao
Z
Li
Huihui
H
Han
Chunyan
C
Li
D000818:Animals; D002460:Cell Line; D003474:Curcumin / Q000031:analogs & derivatives* / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D051547:Heme Oxygenase-1 / Q000096:biosynthesis*; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis*; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation / Q000235:genetics*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology
D003474:Curcumin; D004268:DNA-Binding Proteins; D051547:Heme Oxygenase-1; D008565:Membrane Proteins; D018696:Neuroprotective Agents; C578077:Tardbp protein, mouse; C521105:dimethoxycurcumin; C496542:Hmox1 protein, mouse