ZPR1-Dependent Neurodegeneration Is Mediated by the JNK Signaling Pathway

Overview

Journal J Exp Neurosci

Publisher Sage Publications

Specialty Neurology

Date 2019 Sep 7

PMID 31488953

Citations 11

Authors

Xiaoting Jiang

Annapoorna Kannan

Laxman Gangwani

Affiliations

Soon will be listed here.

Abstract

The zinc finger protein ZPR1 deficiency causes neurodegeneration and results in a mild spinal muscular atrophy (SMA)-like disease in mice with reduced gene dosage. Mutation of the 1 () gene causes SMA. Spinal muscular atrophy is characterized by the degeneration of the spinal cord motor neurons caused by chronic low levels of SMN protein. ZPR1 interacts with SMN and is required for nuclear accumulation of SMN. Patients with SMA express reduced levels of ZPR1. Reduced gene dosage increases neurodegeneration and severity of SMA disease in mice. Mechanisms underlying ZPR1-dependent neurodegeneration are largely unknown. We report that neurodegeneration caused by ZPR1 deficiency is mediated by the c-Jun NH-terminal kinase (JNK) group of mitogen-activated protein kinases (MAPK). ZPR1-dependent neuron degeneration is mediated by central nervous system (CNS)-specific isoform JNK3. ZPR1 deficiency activates the MAPK signaling cascade, MLK3 → MKK7 → JNK3, which phosphorylates c-Jun and activates caspase-mediated neuron degeneration. Neurons from -null mice show resistance to ZPR1-dependent neurodegeneration. Pharmacologic inhibition of JNK reduces degeneration of ZPR1-deficient neurons. These data show that ZPR1-dependent neurodegeneration is mediated by the JNK signaling pathway and suggest that ZPR1 downregulation in SMA may contribute to JNK-mediated neurodegeneration associated with SMA pathogenesis.

Citing Articles

Role of senataxin in R-loop-mediated neurodegeneration.

Kannan A, Gangadharan Leela S, Branzei D, Gangwani L Brain Commun. 2024; 6(4):fcae239.

PMID: 39070547 PMC: 11277865. DOI: 10.1093/braincomms/fcae239.

Pan-Cancer Profiling and Digital Pathology Analysis Reveal Negative Prognostic Biomarker ZPR1 Associated with Immune Infiltration and Treatment Response in Hepatocellular Carcinoma.

He L, Xie Y, Qiu Y, Zhang Y J Hepatocell Carcinoma. 2023; 10:1309-1325.

PMID: 37581094 PMC: 10423584. DOI: 10.2147/JHC.S415224.

The phospho-landscape of the survival of motoneuron protein (SMN) protein: relevance for spinal muscular atrophy (SMA).

Detering N, Schuning T, Hensel N, Claus P Cell Mol Life Sci. 2022; 79(9):497.

PMID: 36006469 PMC: 11071818. DOI: 10.1007/s00018-022-04522-9.

R-loop Mediated DNA Damage and Impaired DNA Repair in Spinal Muscular Atrophy.

Cuartas J, Gangwani L Front Cell Neurosci. 2022; 16:826608.

PMID: 35783101 PMC: 9243258. DOI: 10.3389/fncel.2022.826608.

Mutation in senataxin alters the mechanism of R-loop resolution in amyotrophic lateral sclerosis 4.

Kannan A, Cuartas J, Gangwani P, Branzei D, Gangwani L Brain. 2022; 145(9):3072-3094.

PMID: 35045161 PMC: 9536298. DOI: 10.1093/brain/awab464.

References

Lorson C, Hahnen E, Androphy E, Wirth B . A single nucleotide in the SMN gene regulates splicing and is responsible for spinal muscular atrophy. Proc Natl Acad Sci U S A. 1999; 96(11):6307-11. PMC: 26877. DOI: 10.1073/pnas.96.11.6307. View

Monani U, Lorson C, Parsons D, Prior T, Androphy E, Burghes A . A single nucleotide difference that alters splicing patterns distinguishes the SMA gene SMN1 from the copy gene SMN2. Hum Mol Genet. 1999; 8(7):1177-83. DOI: 10.1093/hmg/8.7.1177. View

Yasuda J, Whitmarsh A, Cavanagh J, Sharma M, Davis R . The JIP group of mitogen-activated protein kinase scaffold proteins. Mol Cell Biol. 1999; 19(10):7245-54. PMC: 84717. DOI: 10.1128/MCB.19.10.7245. View

Davis R . Signal transduction by the JNK group of MAP kinases. Cell. 2000; 103(2):239-52. DOI: 10.1016/s0092-8674(00)00116-1. View

McDonald P, Chow C, Miller W, Laporte S, Field M, Lin F . Beta-arrestin 2: a receptor-regulated MAPK scaffold for the activation of JNK3. Science. 2000; 290(5496):1574-7. DOI: 10.1126/science.290.5496.1574. View

Gangwani L, Mikrut M, Theroux S, Sharma M, Davis R . Spinal muscular atrophy disrupts the interaction of ZPR1 with the SMN protein. Nat Cell Biol. 2001; 3(4):376-83. DOI: 10.1038/35070059. View

Mota M, Reeder M, Chernoff J, Bazenet C . Evidence for a role of mixed lineage kinases in neuronal apoptosis. J Neurosci. 2001; 21(14):4949-57. PMC: 6762862. View

Bennett B, Sasaki D, Murray B, OLeary E, Sakata S, Xu W . SP600125, an anthrapyrazolone inhibitor of Jun N-terminal kinase. Proc Natl Acad Sci U S A. 2001; 98(24):13681-6. PMC: 61101. DOI: 10.1073/pnas.251194298. View

Weston C, Davis R . The JNK signal transduction pathway. Curr Opin Genet Dev. 2002; 12(1):14-21. DOI: 10.1016/s0959-437x(01)00258-1. View

10.

Helmken C, Hofmann Y, Schoenen F, Oprea G, Raschke H, Rudnik-Schoneborn S . Evidence for a modifying pathway in SMA discordant families: reduced SMN level decreases the amount of its interacting partners and Htra2-beta1. Hum Genet. 2003; 114(1):11-21. DOI: 10.1007/s00439-003-1025-2. View

11.

Guan Q, Pei D, Zhang Q, Hao Z, Xu T, Zhang G . The neuroprotective action of SP600125, a new inhibitor of JNK, on transient brain ischemia/reperfusion-induced neuronal death in rat hippocampal CA1 via nuclear and non-nuclear pathways. Brain Res. 2005; 1035(1):51-9. DOI: 10.1016/j.brainres.2004.11.050. View

12.

Gangwani L, Flavell R, Davis R . ZPR1 is essential for survival and is required for localization of the survival motor neurons (SMN) protein to Cajal bodies. Mol Cell Biol. 2005; 25(7):2744-56. PMC: 1061650. DOI: 10.1128/MCB.25.7.2744-2756.2005. View

13.

Monani U . Spinal muscular atrophy: a deficiency in a ubiquitous protein; a motor neuron-specific disease. Neuron. 2005; 48(6):885-96. DOI: 10.1016/j.neuron.2005.12.001. View

14.

Doran B, Gherbesi N, Hendricks G, Flavell R, Davis R, Gangwani L . Deficiency of the zinc finger protein ZPR1 causes neurodegeneration. Proc Natl Acad Sci U S A. 2006; 103(19):7471-5. PMC: 1464363. DOI: 10.1073/pnas.0602057103. View

15.

Roos W, Kaina B . DNA damage-induced cell death by apoptosis. Trends Mol Med. 2006; 12(9):440-50. DOI: 10.1016/j.molmed.2006.07.007. View

16.

Gangwani L . Deficiency of the zinc finger protein ZPR1 causes defects in transcription and cell cycle progression. J Biol Chem. 2006; 281(52):40330-40. DOI: 10.1074/jbc.M608165200. View

17.

Borsello T, Forloni G . JNK signalling: a possible target to prevent neurodegeneration. Curr Pharm Des. 2007; 13(18):1875-86. DOI: 10.2174/138161207780858384. View

18.

Mishra A, Gangwani L, Davis R, Lambright D . Structural insights into the interaction of the evolutionarily conserved ZPR1 domain tandem with eukaryotic EF1A, receptors, and SMN complexes. Proc Natl Acad Sci U S A. 2007; 104(35):13930-5. PMC: 1955815. DOI: 10.1073/pnas.0704915104. View

19.

Burghes A, Beattie C . Spinal muscular atrophy: why do low levels of survival motor neuron protein make motor neurons sick?. Nat Rev Neurosci. 2009; 10(8):597-609. PMC: 2853768. DOI: 10.1038/nrn2670. View

20.

Markowitz J, Singh P, Darras B . Spinal muscular atrophy: a clinical and research update. Pediatr Neurol. 2011; 46(1):1-12. DOI: 10.1016/j.pediatrneurol.2011.09.001. View