Novel tankyrase inhibitors suppress TDP-43 aggregate formation.

Abstract

Transactive response DNA-binding protein of 43 kDa (TDP-43) abnormally forms aggregates in certain subtypes of frontotemporal lobar degeneration (FTLD) and in amyotrophic lateral sclerosis (ALS). The pathological forms of TDP-43 have reported to be associated with poly(ADP-ribose) (PAR), which regulates the properties of these aggregates. A recent study has indicated that tankyrase, a member of the PAR polymerase (PARP) family, regulates pathological TDP-43 formation under conditions of stress, and tankyrase inhibitors suppress TDP-43 aggregate formation and cytotoxicity. Since we reported the development of tankyrase inhibitors that are more specific than conventional inhibitors, in this study, we examined their effects on the formation of TDP-43 aggregates in cultured cells. Time-lapse imaging showed that TDP-43 aggregates appeared in the nucleus within 30 min of treatment with sodium arsenite. Several tankyrase inhibitors suppressed the formation of aggregates and decreased the levels of the tankyrase protein. Immunohistochemical studies demonstrated that tankyrase was localized to neuronal cytoplasmic inclusions in the spinal cords of patients with ALS. Moreover, the tankyrase protein levels were significantly higher in the brains of patients with FTLD than in the brains of control subjects. These findings suggest that the inhibition of tankyrase activity protects against TDP-43 toxicity. Tankyrase inhibitors may be a potential treatment to suppress the progression of TDP-43 proteinopathies.

• Authors: Kunikazu Tanji, Fumiaki Mori, Fumiyuki Shirai, Takehiro Fukami, Hiroyuki Seimiya, Jun Utsumi, Akiyoshi Kakita, Koichi Wakabayashi
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 537 Pg. 85-92 (01 22 2021) ISSN: 1090-2104 [Electronic] United States
• PMID: 33387887 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 Elsevier Inc. All rights reserved.

Chemical References

• Arsenites
• DNA-Binding Proteins
• Enzyme Inhibitors
• Protein Aggregates
• TARDBP protein, human
• Poly Adenosine Diphosphate Ribose
• Tankyrases
• arsenite

Topics

• Arsenites (toxicity)
• Cell Line, Tumor
• Cell Nucleus (drug effects, metabolism)
• DNA-Binding Proteins (metabolism)
• Enzyme Inhibitors (pharmacology)
• HEK293 Cells
• Humans
• Poly Adenosine Diphosphate Ribose (toxicity)
• Protein Aggregates (drug effects)
• TDP-43 Proteinopathies (pathology)
• Tankyrases (antagonists & inhibitors, metabolism)