TDP-43, a protein central to amyotrophic lateral sclerosis, is destabilized by tankyrase-1 and -2

TY - JOUR

T1 - TDP-43, a protein central to amyotrophic lateral sclerosis, is destabilized by tankyrase-1 and -2

AU - McGurk, Leeanne

AU - Rifai, Olivia

AU - Bonini, Nancy M.

N1 - Funding Information: We thank members of the Bonini Lab for insightful comments. Robert G.Kalb at Northwestern University for the TDP-43 and LacZ viral amplicons. Racheal Neve, Director of the Massachusetts General Hospital (MGH) Gene Delivery Technology Core for HSV viral production. This work was funded by Target ALS; the Glenn Foundation and NIH 5R01NS073660, R35NS097275 (N.M.B.). Publisher Copyright: © 2020. Published by The Company of Biologists Ltd.

PY - 2020/6/23

Y1 - 2020/6/23

N2 - In >95% of amyotrophic lateral sclerosis (ALS) and ~45% of frontotemporal degeneration (FTD), the RNA/DNA-binding protein TDP-43 is cleared from the nucleus and abnormally accumulates in the cytoplasm of affected brain cells. Although the cellular triggers of disease pathology remain enigmatic, mounting evidence implicates the poly(ADP-ribose) polymerases (PARPs) in TDP-43 neurotoxicity. Here we show that inhibition of the PARP enzymes Tankyrase 1 and Tankyrase 2 (referred to as Tnks-1/2) protect primary rodent neurons from TDP-43-associated neurotoxicity. We demonstrate that Tnks-1/2 interacts with TDP-43 via a newly defined Tankyrase-binding domain. Upon investigating the functional effect, we find that interaction with Tnks-1/2 inhibits the ubiquitination and proteasomal turnover of TDP-43, leading to its stabilization. We further show that proteasomal turnover of TDP-43 occurs preferentially in the nucleus; our data indicate that Tnks-1/2 stabilizes TDP-43 by promoting cytoplasmic accumulation, which sequesters the protein from nuclear proteasome degradation. Thus, Tnks-1/2 activity modulates TDP-43 and is a potential therapeutic target in diseases associated with TDP-43, such as ALS and FTD.

AB - In >95% of amyotrophic lateral sclerosis (ALS) and ~45% of frontotemporal degeneration (FTD), the RNA/DNA-binding protein TDP-43 is cleared from the nucleus and abnormally accumulates in the cytoplasm of affected brain cells. Although the cellular triggers of disease pathology remain enigmatic, mounting evidence implicates the poly(ADP-ribose) polymerases (PARPs) in TDP-43 neurotoxicity. Here we show that inhibition of the PARP enzymes Tankyrase 1 and Tankyrase 2 (referred to as Tnks-1/2) protect primary rodent neurons from TDP-43-associated neurotoxicity. We demonstrate that Tnks-1/2 interacts with TDP-43 via a newly defined Tankyrase-binding domain. Upon investigating the functional effect, we find that interaction with Tnks-1/2 inhibits the ubiquitination and proteasomal turnover of TDP-43, leading to its stabilization. We further show that proteasomal turnover of TDP-43 occurs preferentially in the nucleus; our data indicate that Tnks-1/2 stabilizes TDP-43 by promoting cytoplasmic accumulation, which sequesters the protein from nuclear proteasome degradation. Thus, Tnks-1/2 activity modulates TDP-43 and is a potential therapeutic target in diseases associated with TDP-43, such as ALS and FTD.

KW - ALS

KW - FTD

KW - PARP

KW - Poly(ADP-ribose)

KW - Proteasome

KW - Ubiquitin

UR - https://www.scopus.com/pages/publications/85086971744

U2 - 10.1242/jcs.245811

DO - 10.1242/jcs.245811

M3 - Article

C2 - 32409565

SN - 0021-9533

VL - 133

JO - Journal of Cell Science

JF - Journal of Cell Science

IS - 12

M1 - jcs245811

ER -