A Functional Deficiency of TERA/VCP/p97 Contributes to Impaired DNA Repair in Multiple Polyglutamine Diseases

Overview

Journal Nat Commun

Specialty Biology

Date 2013 May 9

PMID 23652004

Citations 41

Authors

Kyota Fujita

Yoko Nakamura

Tsutomu Oka

Hikaru Ito

Takuya Tamura

Kazuhiko Tagawa

Toshikazu Sasabe

Asuka Katsuta

Kazumi Motoki

Hiroki Shiwaku

Masaki Sone

Chisato Yoshida

Masahisa Katsuno

Yoshinobu Eishi

Miho Murata

J Paul Taylor

Erich E Wanker

Kazuteru Kono

Satoshi Tashiro

Gen Sobue

Albert R La Spada

Hitoshi Okazawa

Affiliations

Soon will be listed here.

Abstract

It is hypothesized that a common underlying mechanism links multiple neurodegenerative disorders. Here we show that transitional endoplasmic reticulum ATPase (TERA)/valosin-containing protein (VCP)/p97 directly binds to multiple polyglutamine disease proteins (huntingtin, ataxin-1, ataxin-7 and androgen receptor) via polyglutamine sequence. Although normal and mutant polyglutamine proteins interact with TERA/VCP/p97, only mutant proteins affect dynamism of TERA/VCP/p97. Among multiple functions of TERA/VCP/p97, we reveal that functional defect of TERA/VCP/p97 in DNA double-stranded break repair is critical for the pathology of neurons in which TERA/VCP/p97 is located dominantly in the nucleus in vivo. Mutant polyglutamine proteins impair accumulation of TERA/VCP/p97 and interaction of related double-stranded break repair proteins, finally causing the increase of unrepaired double-stranded break. Consistently, the recovery of lifespan in polyglutamine disease fly models by TERA/VCP/p97 corresponds well to the improvement of double-stranded break in neurons. Taken together, our results provide a novel common pathomechanism in multiple polyglutamine diseases that is mediated by DNA repair function of TERA/VCP/p97.

Citing Articles

Loss of function of VCP/TER94 causes neurodegeneration.

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Valosin-Containing Protein (VCP): A Review of Its Diverse Molecular Functions and Clinical Phenotypes.

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Valosin containing protein (VCP): initiator, modifier, and potential drug target for neurodegenerative diseases.

Chu S, Xie X, Payan C, Stochaj U Mol Neurodegener. 2023; 18(1):52.

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References

Pleasure I, Black M, Keen J . Valosin-containing protein, VCP, is a ubiquitous clathrin-binding protein. Nature. 1993; 365(6445):459-62. DOI: 10.1038/365459a0. View

Custer S, Neumann M, Lu H, Wright A, Taylor J . Transgenic mice expressing mutant forms VCP/p97 recapitulate the full spectrum of IBMPFD including degeneration in muscle, brain and bone. Hum Mol Genet. 2010; 19(9):1741-55. DOI: 10.1093/hmg/ddq050. View

Tsvetkov A, Miller J, Arrasate M, Wong J, Pleiss M, Finkbeiner S . A small-molecule scaffold induces autophagy in primary neurons and protects against toxicity in a Huntington disease model. Proc Natl Acad Sci U S A. 2010; 107(39):16982-7. PMC: 2947884. DOI: 10.1073/pnas.1004498107. View

Meerang M, Ritz D, Paliwal S, Garajova Z, Bosshard M, Mailand N . The ubiquitin-selective segregase VCP/p97 orchestrates the response to DNA double-strand breaks. Nat Cell Biol. 2011; 13(11):1376-82. DOI: 10.1038/ncb2367. View

Koike M, Fukushi J, Ichinohe Y, Higashimae N, Fujishiro M, Sasaki C . Valosin-containing protein (VCP) in novel feedback machinery between abnormal protein accumulation and transcriptional suppression. J Biol Chem. 2010; 285(28):21736-49. PMC: 2898386. DOI: 10.1074/jbc.M109.099283. View

Katsuno M, Adachi H, Kume A, Li M, Nakagomi Y, Niwa H . Testosterone reduction prevents phenotypic expression in a transgenic mouse model of spinal and bulbar muscular atrophy. Neuron. 2002; 35(5):843-54. DOI: 10.1016/s0896-6273(02)00834-6. View

Ye Y, Shibata Y, Yun C, Ron D, Rapoport T . A membrane protein complex mediates retro-translocation from the ER lumen into the cytosol. Nature. 2004; 429(6994):841-7. DOI: 10.1038/nature02656. View

Lim J, Hao T, Shaw C, Patel A, Szabo G, Rual J . A protein-protein interaction network for human inherited ataxias and disorders of Purkinje cell degeneration. Cell. 2006; 125(4):801-14. DOI: 10.1016/j.cell.2006.03.032. View

Kittler R, Putz G, Pelletier L, Poser I, Heninger A, Drechsel D . An endoribonuclease-prepared siRNA screen in human cells identifies genes essential for cell division. Nature. 2004; 432(7020):1036-40. DOI: 10.1038/nature03159. View

10.

Zhang L, Ashendel C, Becker G, Morre D . Isolation and characterization of the principal ATPase associated with transitional endoplasmic reticulum of rat liver. J Cell Biol. 1994; 127(6 Pt 2):1871-83. PMC: 2120312. DOI: 10.1083/jcb.127.6.1871. View

11.

Chai Y, Shao J, Miller V, Williams A, Paulson H . Live-cell imaging reveals divergent intracellular dynamics of polyglutamine disease proteins and supports a sequestration model of pathogenesis. Proc Natl Acad Sci U S A. 2002; 99(14):9310-5. PMC: 123137. DOI: 10.1073/pnas.152101299. View

12.

Weihl C, Miller S, Hanson P, Pestronk A . Transgenic expression of inclusion body myopathy associated mutant p97/VCP causes weakness and ubiquitinated protein inclusions in mice. Hum Mol Genet. 2007; 16(8):919-28. DOI: 10.1093/hmg/ddm037. View

13.

Manno A, Noguchi M, Fukushi J, Motohashi Y, Kakizuka A . Enhanced ATPase activities as a primary defect of mutant valosin-containing proteins that cause inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia. Genes Cells. 2010; 15(8):911-22. DOI: 10.1111/j.1365-2443.2010.01428.x. View

14.

Ye Y, Meyer H, Rapoport T . The AAA ATPase Cdc48/p97 and its partners transport proteins from the ER into the cytosol. Nature. 2001; 414(6864):652-6. DOI: 10.1038/414652a. View

15.

Acs K, Luijsterburg M, Ackermann L, Salomons F, Hoppe T, Dantuma N . The AAA-ATPase VCP/p97 promotes 53BP1 recruitment by removing L3MBTL1 from DNA double-strand breaks. Nat Struct Mol Biol. 2011; 18(12):1345-50. DOI: 10.1038/nsmb.2188. View

16.

Kim S, Nollen E, Kitagawa K, Bindokas V, Morimoto R . Polyglutamine protein aggregates are dynamic. Nat Cell Biol. 2002; 4(10):826-31. DOI: 10.1038/ncb863. View

17.

Crews L, Spencer B, Desplats P, Patrick C, Paulino A, Rockenstein E . Selective molecular alterations in the autophagy pathway in patients with Lewy body disease and in models of alpha-synucleinopathy. PLoS One. 2010; 5(2):e9313. PMC: 2824828. DOI: 10.1371/journal.pone.0009313. View

18.

Rabouille C, Levine T, Peters J, Warren G . An NSF-like ATPase, p97, and NSF mediate cisternal regrowth from mitotic Golgi fragments. Cell. 1995; 82(6):905-14. DOI: 10.1016/0092-8674(95)90270-8. View

19.

Boland B, Kumar A, Lee S, Platt F, Wegiel J, Yu W . Autophagy induction and autophagosome clearance in neurons: relationship to autophagic pathology in Alzheimer's disease. J Neurosci. 2008; 28(27):6926-37. PMC: 2676733. DOI: 10.1523/JNEUROSCI.0800-08.2008. View

20.

Wheeler V, Auerbach W, White J, Srinidhi J, Auerbach A, Ryan A . Length-dependent gametic CAG repeat instability in the Huntington's disease knock-in mouse. Hum Mol Genet. 1999; 8(1):115-22. DOI: 10.1093/hmg/8.1.115. View