Activation of Transforming Growth Factor-beta/Smad Signaling Reduces Aggregate Formation of Mislocalized TAR DNA-Binding Protein-43

作者：Nakamura Masataka; Kaneko Satoshi^*; Ito Hidefumi; Jiang Shiwen; Fujita Kengo; Wate Reika; Nakano Satoshi; Fujisawa Jun ichi; Kusaka Hirofumi

来源：Neurodegenerative Diseases, 2013, 11(4): 182-193.

DOI：10.1159/000338151

• Amyotrophic lateral sclerosis
• Aggregation Smad
• TAR DNA-binding protein-43
• Transforming growth factor-beta

Background: TAR DNA-binding protein of 43 kDa (TDP-43) is naturally located in the nucleus and has been identified as the major component of cytoplasmic ubiquitinated inclusions in patients with a myotrophic lateral sclerosis (ALS). We have reported that TDP-43 and phosphorylated Smad2 (pSmad2), an intracellular mediator protein of transforming growth factor-beta (TGF beta) signaling, are co-localized within cytoplasmic inclusions in the anterior horn cells of sporadic ALS patients. Objective: To investigate the possible pathophysiological linkage between pathologic cytoplasmic inclusions containing TDP-43 and TGF beta/Smad signaling. Methods: We replicated cytoplasmic aggregates of TDP-43 in HEK293T cells by transfecting the cells with a nuclear localization signal deletion mutant of TDP-43 and inhibiting proteasome activity, and assessed the effect of TGF beta/Smad signaling on the cytoplasmic aggregate formation. Results: The aggregates contained ubiquitinated, phosphorylated, and fragmented TDP-43, consistent with the essential features of the human pathology. Moreover, the aggregates were co-localized with pSmad2 under continuous TGF beta stimulation. Overexpression of Smad2 reduced the amount of cytoplasmic aggregates in HEK293T cells, and TGF beta stimulation augmented this reduction effect in a dose-dependent manner. Conclusion: Activation of the TGF beta/Smad signaling system is protective against aggregate formation of cytoplasmically mislocalized TDP-43 and may be a potential therapeutic approach to delay progression of ALS.

• 出版日期2013