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 func- tions 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. Further- more, 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.