%0 Generic
%A M., Nakamura
%A S., Kaneko
%A H., Ito
%A S., Jiang
%A K., Fujita
%A R., Wate
%A S., Nakano
%A J., Fujisawa
%A H., Kusaka
%D 2012
%T Supplementary Material for: Activation of Transforming Growth Factor-β/Smad Signaling Reduces Aggregate Formation of Mislocalized TAR DNA-Binding Protein-43
%U https://karger.figshare.com/articles/dataset/Supplementary_Material_for_Activation_of_Transforming_Growth_Factor-_Smad_Signaling_Reduces_Aggregate_Formation_of_Mislocalized_TAR_DNA-Binding_Protein-43/5123491
%R 10.6084/m9.figshare.5123491.v1
%2 https://karger.figshare.com/ndownloader/files/8709313
%2 https://karger.figshare.com/ndownloader/files/8709316
%2 https://karger.figshare.com/ndownloader/files/8709319
%K Amyotrophic lateral sclerosis
%K Aggregation
%K Smad
%K TAR DNA-binding protein-43
%K Transforming growth factor-β
%X 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 amyotrophic lateral sclerosis (ALS). We have reported that TDP-43 and phosphorylated Smad2 (pSmad2), an intracellular mediator protein of transforming growth factor-β (TGFβ) 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 TGFβ/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 TGFβ/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 TGFβ stimulation. Overexpression of Smad2 reduced the amount of cytoplasmic aggregates in HEK293T cells, and TGFβ stimulation augmented this reduction effect in a dose-dependent manner. Conclusion: Activation of the TGFβ/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.
%I Karger Publishers