TRIM9 and TRIM67 Are New Targets in Paraneoplastic Cerebellar Degeneration
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.
KeywordsTRIM9 TRIM67 Autoantibodies Lung cancer Paraneoplastic cerebellar disorders
We thank Professor Casper Hoogenraad, Faculty of Science, Utrecht University for providing us with the Trim46 plasmid construct.
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
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.
- 4.Ducray F, Demarquay G, Graus F, Decullier E, Antoine JC, Giometto B, et al. Seronegative paraneoplastic cerebellar degeneration: the PNS Euronetwork experience. Eur J Neurol. 2014 May;21(5):731–5.Google Scholar
- 6.Boyer NP, Monkiewicz C, Menon S, Moy SS, Gupton SL. Mammalian TRIM67 functions in brain development and behavior. eNeuro. 2018;5(3):ENEURO.0186–18.2018.Google Scholar
- 8.Menon S, Boyer NP, Winkle CC, McClain LM, Hanlin CC, Pandey D, et al. The E3 ubiquitin ligase TRIM9 is a filopodia off switch required for netrin-dependent axon guidance. Dev Cell. 2015;35(6):698–712.Google Scholar
- 10.Van Coevorden-Hameete MH, van Beuningen SFB, Perrenoud M, Will LM, Hulsenboom E, Demonet JF, et al. Antibodies to TRIM46 are associated with paraneoplastic neurological syndromes. Ann Clin Transl Neurol. 2017;4(9):680–6.Google Scholar
- 12.Larman HB, Zhao Z, Laserson U, Li MZ, Ciccia A, Gakidis MA, et al. Autoantigen discovery with a synthetic human peptidome. Nat Biotechnol. 2011;29(6):535–41.Google Scholar
- 17.Plooster M, Menon S, Winkle CC, Urbina FL, Monkiewicz C, Phend KD, et al. TRIM9-dependent ubiquitination of DCC constrains kinase signaling, exocytosis, and axon branching. Molecular Biology of the Cell. 2017;28(18):2374–85.Google Scholar
- 20.Do LD, Chanson E, Desestret V, Joubert B, Ducray F, Brugière S, et al. Characteristics in limbic encephalitis with anti-adenylate kinase 5 autoantibodies. Neurology. 2017;88(6):514–24.Google Scholar