Background:The highly flexible C-terminal region of TDP-43 is implicated in disease pathology. Results: An amyloidogenic core was identified to be critical for TDP-43 aggregation. Conclusion: Helix-to-sheet structural transformation of the amyloidogenic core initiates TDP-43 aggregation and cytoplasmic inclusion formation. Significance: This is a potential therapeutic target for mitigating the TDP-43 proteinopathies.

Reactive oxygen species (ROS) have important roles in normal physiology and diseases, particularly cancer. Under normal physiological conditions, they participate in redox reactions and serve as second messengers for regulatory functions. Owing to aberrant metabolism, cancer cells accumulate excessive ROS, thus requiring a robustly active antioxidant system to prevent cellular damage. Superoxide dismutases (SODs) are enzymes that catalyze the removal of superoxide free radicals. There are three distinct members of this metalloenzyme family in mammals: SOD1 (Cu/ZnSOD), SOD2 (MnSOD) and SOD3 (ecSOD). SODs are increasingly recognized for their regulatory functions in growth, metabolism and oxidative stress responses, which are also crucial for cancer development and survival. Growing evidence shows that SODs are also potentially useful anticancer drug targets. This review will focus on recent research of SODs in cellular regulation, with emphasis on their roles in cancer biology and therapy.

TAR DNA binding protein of 43 kDa (TDP-43) is a nuclear factor functioning in RNA processing. It is also a major deposited protein in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin (FTLD-U). To understand the mechanism underlying the inclusion body formation and possible functional alteration, we studied some TDP-43 fragments and their effects on RNA processing in cell models. The results show that the 35-kDa fragment of TDP-43 (namely TDP-35, residues 90-414), but not TDP-25A (184-414), is capable of forming cytoplasmic inclusion bodies and altering pre-mRNA splicing. The inclusions formed by TDP-35 can also recruit full-length TDP-43 to cytoplasmic deposition from functionally nuclear localization. The in vitro studies demonstrate that TDP-35, rather than TDP-43 and TDP-25A, is prone to aggregation, and it further serves as a seed to facilitate aggregation of full-length TDP-43. This suggests that fragmentation of TDP-43 leads to cellular redistribution, inclusion body formation, and altered RNA processing, which are implicated in the molecular pathogenesis of ALS and FTLD.