黑料吃瓜资源

Paraneoplastic Neurological Syndromes (PNS) research group

Paraneoplastic syndromes of the nervous system are rare immune-mediated disorders that manifest in individuals with cancer. PNS develops when the immune system's cancer-fighting agents inadvertently attack parts of the brain, spinal cord, peripheral nerves, or muscles, leading to neurodegeneration. Our focus lies on understanding the most prevalent type of PNS: Paraneoplastic Cerebellar Degeneration (PCD).

PNS
Photo: PNS

About the research group

PCD serves as an autoimmune model for neurodegeneration linked to breast, ovarian, or other gynecological cancers, predominantly affecting women. Onconeuronal Yo autoantibodies, detectable in both serum and cerebrospinal fluid of PCD patients, target cancer cells and Purkinje neurons in the cerebellum. These antibodies contribute to neuronal dysfunction and Purkinje neuron death by interacting with intracellular cerebellar degeneration-related antigens鈥擟DR2 and CDR2Like鈥攅xpressed ectopically in tumor cells and endogenously in Purkinje neurons.

Advancing Neuroprotective Therapies:

Our primary objective is to pioneer a neuroprotective therapy by delving into the molecular mechanisms that trigger neurodegeneration. The current therapeutic approach involves tumor removal to prevent further neuronal damage. However, PCD symptoms often precede cancer diagnosis, and tumors are frequently too small to be localized at that stage, complicating this treatment. Unfortunately, there is currently no other effective treatment available to counteract the induced neurodegeneration.

Over the past years, we've made significant strides in developing two artificial PCD ex-vivo systems. These innovative systems enable us to observe biochemical cascades both before and after the intake of Yo autoantibodies in the specifically targeted Purkinje neurons of the cerebellum. Through these approaches, we aim to gain valuable insights into the intricate processes underlying neurodegeneration, ultimately paving the way for effective and targeted neuroprotective interventions.

Research areas

Our focus areas are paraneoplastic neurological syndromes and paraneoplastic cerebellar degeneration.

PNS group, 黑料吃瓜资源
Photo: PNS group, 黑料吃瓜资源


Fig 1: Proposed mechanism for PNS: A tumour expresses onconeural antigens. Dendritic cells engulf apoptotic tumour cells and migrate to the lymph node where tumour antigens are presented to the immune system with subsequent activation of B- and T-cells. Activated B cells differentiate into antibody-secreting plasma cells that produce onconeural antibodies. Antibodies and cytotoxic T cells slow the growth of the tumour, but antibodies, plasma cells and cytotoxic T-cells can also cross the blood-brain barrier and target neurons that express these proteins.

Paraneoplastic neurological syndromes


Paraneoplastic neurological syndromes (PNS) are rare side effects of cancer that occur in less than 1 % of all cancer patients. It is most often associated with small-cell lung cancer, ovarian cancer and breast cancer. Detection of paraneoplastic antibodies is an important tool to diagnose PNS and the underlying cancer since the clinical manifestations often appear early in cancer development, while the tumour is still small. The type of antibody can give indications about the localization of the tumour. This means that the tumour can be identified at an earlier stage, specific cancer treatment can be started, and the chance for better recovery is increased.

The mechanism of PNS is largely unknown, but often the tumour expresses proteins that are normally only expressed in the nervous system. The immune system does not recognize these proteins from immune privileged sites as its own and produces antibodies and activates T-cells directed towards these proteins in an attempt to control tumour growth. Antibodies and T-cells cross the blood-brain barrier and react with proteins in the nervous system. This leads to loss of neurons and development of neurological syndromes.
 

Paraneoplastic cerebellar degeneration


Paraneoplastic cerebellar degeneration (PCD) is one of the best described forms of PNS. It mainly affects women with gynaecological or breast cancer. Anti-Yo is the antibody that is associated with PCD. PCD is caused by loss of Purkinje cells in the cerebellum, leading to severe cerebellar dysfunctions such as diplopia, dysarthria, tremor and ataxia and ultimately death. Some studies imply that Yo antibodies can cause Purkinje cell death, but the mechanism behind this process is yet unknown. Recent results from our laboratory suggest that Purkinje cell death is related to Yo antibodies by altering the Ca2+-balance in the cells, leading to 鈥渄ark cell degeneration鈥. Yo antibodies have been found to recognize members of the so called cerebellar degeneration related (CDR) proteins. There are 3 known CDR proteins, namely CDR1, CDR2 and CDR2L. We have shown that Yo antibodies mainly recognize the CDR2 and CDR2L proteins, but sera from patients with PCD may also recognize CDR1.

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Recognition

The group was evaluated as 鈥渧ery good鈥 by the Norwegian Research Council in 2011, and was part of the Helse Vest Research Prize in 2012 and the University of Bergen Research Prize in 2013.

Projects

Publications

Recent Impactful Publications (2019-Present):

1) Nes MS, Haugen M, Haugland HK, Gilhus NE, Vedeler CA. Case report: Seropositive myasthenia gravis complicated by limbic encephalitis positive for antibodies to AMPAR and Lgi1. Front Neurol. 2023 Oct 12;14:1237140. doi: 10.3389/fneur.2023.1237140. 

2) Erikstad KI, Herdlevaer I, Peter E, Haugen M, Totland C, Vedeler C. A cerebellar degeneration-related protein 2-like cell-based assay for anti-Yo detection in patients with paraneoplastic cerebellar degeneration. Eur J Neurol. 2023 Jun;30(6):1727-1733. doi: 10.1111/ene.15786. 

3) Uggerud IM, Kr氓kenes T, Hirai H, Vedeler CA, Schubert M. Development and Optimization of a Multilayer Rat Purkinje Neuron Culture. Cerebellum. 2023 Jan 10. doi: 10.1007/s12311-022-01510-4. 

4) Greenlee JE, Carlson NG, Abbatemarco JR, Herdlev忙r I, Clardy SL, Vedeler CA. Editorial: Autoimmunity and the Brain: Paraneoplastic Neurological Injury and Beyond. Front Neurol. 2022 May 12;13:900130. doi: 10.3389/fneur.2022.900130. 

5) Greenlee JE, Carlson NG, Abbatemarco JR, Herdlev忙r I, Clardy SL, Vedeler CA. Paraneoplastic and Other Autoimmune Encephalitides: Antineuronal Antibodies, T Lymphocytes, and Questions of Pathogenesis. Front Neurol. 2022 Jan 17;12:744653. doi: 10.3389/fneur.2021.744653. 

6) Raspotnig M, Kr氓kenes T, Herdlev忙r I, Haugen M, Vedeler C. Expression of cerebellar degeneration-related proteins CDR2 and CDR2L in human and rat brain tissue. J Neuroimmunol. 2022 Jan 15;362:577766. doi: 10.1016/j.jneuroim.2021.577766. 

7) Totland C, Haugen M,鈥疺edeler C. CRMP5 Antibodies-Diagnostic Challenges. Front Neurol. 2021 Sep 22;12:729075. doi: 10.3389/fneur.2021.729075. 

8) Graus F, Vogrig A, Mu帽iz-Castrillo S, Antoine JG, Desestret V, Dubey D, Giometto B, Irani SR, Joubert B, Leypoldt F, McKeon A, Pr眉ss H, Psimaras D, Thomas L, Titulaer MJ, Vedeler CA, Verschuuren JJ, Dalmau J, Honnorat J. Updated Diagnostic Criteria for Paraneoplastic Neurologic Syndromes. Neurol Neuroimmunol Neuroinflamm. 2021 May 18;8(4):e1014. doi: 10.1212/NXI.0000000000001014. 

9) Herdlev忙r I, Haugen M, Mazengia K, Totland C, Vedeler C. Paraneoplastic Cerebellar Degeneration: The Importance of Including CDR2L as a Diagnostic Marker. Neurol Neuroimmunol Neuroinflamm. 2021 Feb 2;8(2):e963. doi: 10.1212/NXI.0000000000000963. 

10) Varhaug KN, Hikmat O, Nakkestad HL, Vedeler CA, Bindoff LA. Serum biomarkers in primary mitochondrial disorders. Brain Commun. 2021 Jan 4;3(1):fcaa222. doi: 10.1093/braincomms/fcaa222. 

11) Herdlevaer I, Kr氓kenes T, Schubert M, Vedeler CA. Localization of CDR2L and CDR2 in paraneoplastic cerebellar degeneration. Ann Clin Transl Neurol. 2020 Nov;7(11):2231-2242. doi: 10.1002/acn3.51212. 

12) Kr氓kenes T, Herdlevaer I, Raspotnig M, Haugen M, Schubert M, Vedeler CA. CDR2L Is the Major Yo Antibody Target in Paraneoplastic Cerebellar Degeneration. Ann Neurol. 2019 Aug;86(2):316-321. doi: 10.1002/ana.25511. Epub 2019 Jun 13. 

 

 

Classic Contributions:

  • Totland C, Kr氓kenes T, Mazengia K, Haugen M, Vedeler CA. Expression of the onconeural protein CDR1 in cerebellum and ovarian cancer. Oncotarget 2018 May 8;9(35):23975鈥23986. [doi: 10.18632/oncotarget.25252]
     
  • Panja D, Vedeler CA, Schubert M. Paraneoplastic cerebellar degeneration: Yo antibody alters mitochondrial calcium buffering capacity. Neuropathol Appl Neurobiol. 2018 Apr 21. [doi: 10.1111/nan.12492]
     
  • Eichler TW, Totland C, Haugen M, Vedeler CA. CCDC104 Antibodies and Mitosis of Cancer Cells. Scand J Immunol. 2018 Feb;87(2):109-110. [doi: 10.1111/sji.12634]
     
  • Raspotnig M, Haugen M, Thorsteinsdottir M, Stefansson I, Salvesen HB, Storstein A, Vedeler CA. Cerebellar degeneration-related proteins 2 and 2-like are present in ovarian cancer in patients with and without Yo antibodies. Cancer Immunol Immunother. 2017 Nov;66(11):1463-1471. [doi: 10.1007/s00262-017-2041-8]
     
  • Storstein A, Raspotnig M, Vitaliani R, Giometto B, Graus F, Grisold W, Honnorat J, Vedeler CA. Prostate cancer, Hu antibodies and paraneoplastic neurological syndromes. J Neurol. 2016 May;263(5):1001-7. []
     
  • Haukanes BI, Hegvik TA, Eichler T, Haavik J, Vedeler CA. Paraneoplastic syndrome-associated neuronal antibodies in adult ADHD. J Neuroimmunol. 2015 Nov 15;288:87-91. []
     
  • Schubert M, Panja D, Haugen M, Bramham CR, Vedeler CA. Paraneoplastic CDR2 and CDR2L antibodies affect Purkinje cell calcium homeostasis. Acta Neuropathol (2014) 128:835鈥852. []
     
  • Eichler TW, Totland C, Haugen M, Qvale TH, Mazengia K, Storstein A, Haukanes BI, Vedeler CA. CDR2L antibodies: a new player in paraneoplastic cerebellar degeneration. PLoS One. 2013 Jun 18;8(6). []
     
  • Totland C, Ying M, Haugen M, Mazengia K, Storstein A, Aarseth J, Martinez A, Vedeler CA. Avidity of onconeural antibodies is of clinical relevance. Cancer Immunol Immunother. 2013 Aug;62(8):1393-6. []
     
  • Tzoulis C, Vedeler C, Haugen M, Storstein A, Tran GT, Gjerde IO, Biermann M, Schwarzlm眉ller T, Bindoff LA. Progressive striatal necrosis is associated with anti-NMDAR antibodies. BMC Neurol. 2013, 31;13:55. []
     
  • Olberg H, Haugen M, Storstein A, Vedeler CA. Neurological manifestations related to level of voltage-gated potassium channel antibodies. J Neurol Neurosurg Psychiatry. 2013, 84(8):941-3. []
     
  • Giometto B, Vitaliani R, Lindeck-Pozza E, Grisold W, Vedeler CA. Treatment for paraneoplastic neuropathies. Cochrane Database Syst Rev. 2012 Dec 12;12. []
     
  • Trier NH, Hansen PR, Vedeler CA, Somnier FE, Houen G. Identification of continuous epitopes of HuD antibodies related to paraneoplastic diseases/small cell lung cancer. J Neuroimmunol. 2012 Feb 29;243(1-2):25-33. []
     
  • Raspotnig M, Vedeler CA, Storstein A. Onconeural antibodies in patients with neurological symptoms: detection and clinical significance. Acta Neurol Scand Suppl 2011; 191: 83-8. []
     
  • Vigliani MC, Honnorat J, Antoine JC, Vialiani R, Giometto B, Psimaras D, Franchino F, Rossi C, Graus F; PNS EuroNetwork. Chorea and related movement disorders of paraneoplastic origin: the PNS EuroNetwork experience. J Neurol 2011; 258: 2058-68. []
     
  • S酶rensen PS, Jensen PE, Haghikia A, Lundkvist M, Vedeler CA, Sellebjerg F, Koch-Henriksen N, Fogdell-Hahn A, Myhr KM, Hillert J, Gold R. Occurrence of antibodies against natalizumab in relapsing multiple sclerosis patients treated with natalizumab. Mult Scler. 2011; 17: 1074-8. []
     
  • Briani C, Vitaliani R, Grisold W, Honnorat J, Graus F, Antoine JC, Bertolini G, Giometto B; PNS Euronetwork. Spectrum of paraneoplastic disease associated with lymphoma. Neurology. 2011;76:705-10. []
     
  • Totland C, Aarskog NK, Eichler TW, Haugen M, Haukanes BI, Vedeler CA. CDR2 antigen and Yo antibodies. Cancer Immunol Immunother 2011; 60:283-9. []
     
  • Titulaer MJ, Soffietti R, Dalmau J, Gilhus NE, Giometto B, Graus F, Grisold W, Honnorat J, Sillevis Smitt PA, Tanasescu R, Vedeler CA, Voltz R, Verschuuren JJ. Screening for tumours in paraneoplastic syndromes: report of an EFNS task force. Eur J Neurol. 2011 Jan 18 [Epub ahead of print]. [] 
     
  • Storstein A, Monstad S, Haugen M et al. Onconeural antibodies: improved detection and clinical correlations. J Neuroimmunol. 2011;232:166-70. []

 

People

Group manager

Christian A. Vedeler, Prof, MD, PhD

Group members

Manja Schubert Senior Researcher, ScD

Cecilie Totland Postdoctoral Researcher, PhD

Postdoctoral Researcher, PhD

Margrethe Raspotnig Consultant Neurologist, MD, PhD student

Torbj酶rn Kr氓kenes Group member

Mette Haugen Staff Engineer

Kibret Mazengia Microbiologist & Staff Engineer

Ida Herdlev忙r Group member

Ida Uggerud group member

Eirik Solheim Group member