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1.
Biochem Biophys Res Commun ; 537: 85-92, 2021 01 22.
Article En | MEDLINE | ID: mdl-33387887

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.


DNA-Binding Proteins/metabolism , Enzyme Inhibitors/pharmacology , Protein Aggregates , Tankyrases/antagonists & inhibitors , Arsenites/toxicity , Cell Line, Tumor , Cell Nucleus/drug effects , Cell Nucleus/metabolism , HEK293 Cells , Humans , Poly Adenosine Diphosphate Ribose/toxicity , Protein Aggregates/drug effects , TDP-43 Proteinopathies/pathology , Tankyrases/metabolism
2.
Proc Natl Acad Sci U S A ; 103(48): 18308-13, 2006 Nov 28.
Article En | MEDLINE | ID: mdl-17116882

Excessive activation of the nuclear enzyme, poly(ADP-ribose) polymerase-1 (PARP-1) plays a prominent role in various of models of cellular injury. Here, we identify poly(ADP-ribose) (PAR) polymer, a product of PARP-1 activity, as a previously uncharacterized cell death signal. PAR polymer is directly toxic to neurons, and degradation of PAR polymer by poly(ADP-ribose) glycohydrolase (PARG) or phosphodiesterase 1 prevents PAR polymer-induced cell death. PARP-1-dependent, NMDA excitotoxicity of cortical neurons is reduced by neutralizing antibodies to PAR and by overexpression of PARG. Neuronal cultures with reduced levels of PARG are more sensitive to NMDA excitotoxicity than WT cultures. Transgenic mice overexpressing PARG have significantly reduced infarct volumes after focal ischemia. Conversely, mice with reduced levels of PARG have significantly increased infarct volumes after focal ischemia compared with WT littermate controls. These results reveal PAR polymer as a signaling molecule that induces cell death and suggests that interference with PAR polymer signaling may offer innovative therapeutic approaches for the treatment of cellular injury.


Apoptosis/drug effects , Poly Adenosine Diphosphate Ribose/toxicity , Polymers/toxicity , Signal Transduction , Animals , Caspases/metabolism , Cells, Cultured , Mice , Molecular Weight , Neurons/drug effects , Poly Adenosine Diphosphate Ribose/chemistry , Poly(ADP-ribose) Polymerases/metabolism , Polymers/chemistry
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