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TRIM9 and TRIM67 Are New Targets in Paraneoplastic Cerebellar Degeneration

  • Le Duy Do
  • Stephanie L. Gupton
  • Kunikazu Tanji
  • Joubert Bastien
  • Sabine Brugière
  • Yohann Couté
  • Isabelle Quadrio
  • Veronique Rogemond
  • Nicole Fabien
  • Virginie Desestret
  • Jerome Honnorat
Original Paper

Abstract

To describe autoantibodies (Abs) against tripartite motif-containing (TRIM) protein 9 and 67 in two patients with paraneoplastic cerebellar degeneration (PCD) associated with lung adenocarcinoma. Abs were characterized using immunohistochemistry, Western blotting, cultures of murine cortical, and hippocampal neurons, immunoprecipitation, mass spectrometry, knockout mice for Trim9 and 67, and cell-based assay. Control samples included sera from 63 patients with small cell lung cancer without any paraneoplastic neurological syndrome, 36 patients with lung adenocarcinoma and PNS, CSF from 100 patients with autoimmune encephalitis, and CSF from 165 patients with neurodegenerative diseases. We found Abs targeting TRIM9 and TRIM67 at high concentration in the serum and the cerebrospinal fluid (CSF) of a 78-year-old woman and a 65-year-old man. Both developed subacute severe cerebellar ataxia. Brain magnetic resonance imaging found no abnormality and no cerebellar atrophy. Both had CSF inflammation with mild pleiocytosis and a few oligoclonal bands. We identified a pulmonary adenocarcinoma, confirming the paraneoplastic neurological syndrome in both patients. They received immunomodulatory and cancer treatments without improvement of cerebellar ataxia, even though both were in remission of their cancer (for more than 10 years in one patient). Anti-TRIM9 and anti-TRIM67 Abs were specific to these two patients. All control serum and CSF samples tested were negative for anti-TRIM9 and 67. Anti-TRIM9 and anti-TRIM67 Abs appeared to be specific biomarkers of PCD and should be added to the panel of antigens tested when this is suspected.

Keywords

TRIM9 TRIM67 Autoantibodies Lung cancer Paraneoplastic cerebellar disorders 

Notes

Acknowledgments

We thank Professor Casper Hoogenraad, Faculty of Science, Utrecht University for providing us with the Trim46 plasmid construct.

Authors’ contribution

Dr. Le Duy DO: acquisition, analysis, and interpretation of the data; drafting the manuscript for intellectual content

Prof. Stephanie L Gupton: generated and provided Trim9−/−, Trim67−/−, and Trim9−/−/Trim67−/− mice, experimental design, acquisition, analysis, and interpretation of the mouse neuron data; critical revision of the manuscript for important intellectual content

Dr. Kunikazu Tanji: provided plasmids coding for different domains of TRIM9

Dr. Joubert Bastien: acquisition and analysis of data

Sabine Brugière and Dr. Yohann Couté: performed mass spectrometry and collected data

Pr. Isabelle Quadrio: provided CSF sample of control group

Dr. Véronique Rogemond: acquisition and analysis of data

Dr. Nicole Fabien: acquisition and analysis of data

Dr. Virginie Desestret: analysis and interpretation, critical revision of the manuscript for important intellectual content, study supervision

Pr Jérôme Honnorat: study concept and design, analysis and interpretation, critical revision of the manuscript for important intellectual content, study supervision

Funding Information

This study was supported by research grants from the Agence Nationale de la Recherche (ANR-14-CE15-0001-MECANO), the Fondation pour la recherche médicale (DQ20170336751), and the National Institutes of Health (GM108970, S.L.G.). Proteomic experiments were partly supported by the Proteomics French Infrastructure (ANR-10-603 INBS-08-01 grant) and Labex GRAL (ANR-10-LABX-49-01).

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Supplementary material

12311_2018_987_MOESM1_ESM.ppt (720 kb)
Supplemental figure S1 Cell-based assay confirming that CSF from patient 1 and CSF from patient 2 were positive for Trim9 and Trim67; they were both negative for TRIM46. (PPT 721 kb)
12311_2018_987_MOESM2_ESM.ppt (408 kb)
Supplemental figure S2 Epitope mapping of anti-TRIM67 Abs. HEK cell were transfected with plasmids coding for different domains of Trim67 and then fixed, permeabilized, and immunolabeled with patient CSF (red) or commercial anti-Myc antibody (green). The Abs are polyclonal since they reacted with different TRIM67 domains. (PPT 408 kb)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Le Duy Do
    • 1
    • 2
    • 3
  • Stephanie L. Gupton
    • 4
  • Kunikazu Tanji
    • 5
  • Joubert Bastien
    • 1
    • 2
    • 3
  • Sabine Brugière
    • 6
  • Yohann Couté
    • 6
  • Isabelle Quadrio
    • 7
  • Veronique Rogemond
    • 1
    • 2
    • 3
  • Nicole Fabien
    • 8
  • Virginie Desestret
    • 1
    • 2
    • 3
  • Jerome Honnorat
    • 1
    • 2
    • 3
    • 9
  1. 1.French Reference Center for Paraneoplastic Neurological SyndromeHospices Civils de Lyon, Hôpital NeurologiqueBronFrance
  2. 2.Institut NeuroMyoGene INSERM U1217/CNRS UMR 5310Université de Lyon - Université Claude Bernard Lyon 1LyonFrance
  3. 3.University of Lyon, Université Claude Bernard Lyon 1LyonFrance
  4. 4.Department of Cell Biology and PhysiologyUniversity of North CarolinaChapel HillUSA
  5. 5.Department of Neuropathology, Institute of Brain ScienceHirosaki University Graduate School of MedicineHirosakiJapan
  6. 6.University Grenoble Alpes, CEA, Inserm, BIG-BGEGrenobleFrance
  7. 7.Neurochemistry Unit, Biochemistry Department, Hospices Civils de LyonGroupement Hospitalier EstBronFrance
  8. 8.Immunology department, Lyon-Sud HospitalHospices Civils de LyonPierre-BéniteFrance
  9. 9.Neuro-OncologieHôpital Neurologique Pierre WertheimerBron CedexFrance

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