Paraneoplastic Cerebellar Degeneration: Yo Antibody Alters Mitochondrial Calcium Buffering Capacity

Overview

Journal Neuropathol Appl Neurobiol

Specialty Neurology

Date 2018 Apr 22

PMID 29679372

Citations 17

Authors

D Panja

C A Vedeler

M Schubert

Affiliations

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Abstract

Aim: Neurodegeneration is associated with dysfunction of calcium buffering capacity and thereby sustained cellular and mitochondrial calcium overload. Paraneoplastic cerebellar degeneration (PCD), characterized by progressive Purkinje neurone degeneration following paraneoplastic Yo antibody internalization and binding to cerebellar degeneration-related protein CDR2 and CDR2L, has been linked to intracellular calcium homeostasis imbalance due to calbindin D malfunction. Therefore, we hypothesized that Yo antibody internalization affects not only calbindin calcium binding capacity, but also calcium-sensitive mitochondrial-associated signalling, causing mitochondrial calcium overload and thereby Purkinje neurone death.

Methods: Immunohistochemically, we evaluated cerebellar organotypic slice cultures of rat brains after inducing PCD through the application of Yo antibody-positive PCD patient sera or purified antibodies against CDR2 and CDR2L how pharmacologically biased mitochondrial signalling affected PCD pathology.

Results: We found that Yo antibody internalization into Purkinje neurons caused depletion of Purkinje neurone calbindin-immunoreactivity, cannabinoid 1 receptor over-activation and alterations in the actions of the mitochondria permeability transition pore (MPTP), voltage-dependent anion channels, reactive oxygen species (ROS) and Na /Ca exchangers (NCX). The pathological mechanisms caused by Yo antibody binding to CDR2 or CDR2L differed between the two targets. Yo-CDR2 binding did not alter the mitochondrial calcium retention capacity, cyclophilin D-independent opening of MPTP or activity of NCX.

Conclusion: These findings suggest that minimizing intracellular calcium overload toxicity either directly with cyclosporin-A or indirectly with cannabidiol or the ROS scavenger butylated hydroxytoluene promotes mitochondrial calcium homeostasis and may therefore be used as future neuroprotective therapy for PCD patients.

Citing Articles

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Tveit Solheim E, Vestrheim Thomsen L, Bjorge L, Anandan S, Peter E, Desestret V Ann Clin Transl Neurol. 2024; 11(12):3255-3266.

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References

Okano H, Park W, Corradi J, Darnell R . The cytoplasmic Purkinje onconeural antigen cdr2 down-regulates c-Myc function: implications for neuronal and tumor cell survival. Genes Dev. 1999; 13(16):2087-97. PMC: 316965. DOI: 10.1101/gad.13.16.2087. View

Sutton I, Steele J, Savage C, Winer J, Young L . An interferon-gamma ELISPOT and immunohistochemical investigation of cytotoxic T lymphocyte-mediated tumour immunity in patients with paraneoplastic cerebellar degeneration and anti-Yo antibodies. J Neuroimmunol. 2004; 150(1-2):98-106. DOI: 10.1016/j.jneuroim.2003.12.026. View

Angelova P, Abramov A . Role of mitochondrial ROS in the brain: from physiology to neurodegeneration. FEBS Lett. 2018; 592(5):692-702. DOI: 10.1002/1873-3468.12964. View

Sakai K, Mitchell D, Tsukamoto T, Steinman L . Isolation of a complementary DNA clone encoding an autoantigen recognized by an anti-neuronal cell antibody from a patient with paraneoplastic cerebellar degeneration. Ann Neurol. 1991; 30(5):738. DOI: 10.1002/ana.410300523. View

Storstein A, Krossnes B, Vedeler C . Morphological and immunohistochemical characterization of paraneoplastic cerebellar degeneration associated with Yo antibodies. Acta Neurol Scand. 2009; 120(1):64-7. DOI: 10.1111/j.1600-0404.2008.01138.x. View

Gajavelli S, Sinha V, Mazzeo A, Spurlock M, Lee S, Ahmed A . Evidence to support mitochondrial neuroprotection, in severe traumatic brain injury. J Bioenerg Biomembr. 2014; 47(1-2):133-48. DOI: 10.1007/s10863-014-9589-1. View

Rimmerman N, Ben-Hail D, Porat Z, Juknat A, Kozela E, Daniels M . Direct modulation of the outer mitochondrial membrane channel, voltage-dependent anion channel 1 (VDAC1) by cannabidiol: a novel mechanism for cannabinoid-induced cell death. Cell Death Dis. 2013; 4:e949. PMC: 3877544. DOI: 10.1038/cddis.2013.471. View

Dahm L, Ott C, Steiner J, Stepniak B, Teegen B, Saschenbrecker S . Seroprevalence of autoantibodies against brain antigens in health and disease. Ann Neurol. 2014; 76(1):82-94. DOI: 10.1002/ana.24189. View

Brana C, Benham C, Sundstrom L . A method for characterising cell death in vitro by combining propidium iodide staining with immunohistochemistry. Brain Res Brain Res Protoc. 2002; 10(2):109-14. DOI: 10.1016/s1385-299x(02)00201-5. View

10.

Darnell J, Albert M, Darnell R . Cdr2, a target antigen of naturally occuring human tumor immunity, is widely expressed in gynecological tumors. Cancer Res. 2000; 60(8):2136-9. View

11.

Roberts W, Darnell R . Neuroimmunology of the paraneoplastic neurological degenerations. Curr Opin Immunol. 2004; 16(5):616-22. DOI: 10.1016/j.coi.2004.07.009. View

12.

Carpenter E, Vance B, Klein R, Voloschin A, Dalmau J, Vonderheide R . Functional analysis of CD8+ T cell responses to the onconeural self protein cdr2 in patients with paraneoplastic cerebellar degeneration. J Neuroimmunol. 2007; 193(1-2):173-82. DOI: 10.1016/j.jneuroim.2007.10.014. View

13.

Panja D, Vedeler C, Schubert M . Paraneoplastic cerebellar degeneration: Yo antibody alters mitochondrial calcium buffering capacity. Neuropathol Appl Neurobiol. 2018; 45(2):141-156. PMC: 7379599. DOI: 10.1111/nan.12492. View

14.

Takanaga H, Mukai H, Shibata H, Toshimori M, Ono Y . PKN interacts with a paraneoplastic cerebellar degeneration-associated antigen, which is a potential transcription factor. Exp Cell Res. 1998; 241(2):363-72. DOI: 10.1006/excr.1998.4060. View

15.

Ling C, Verbny Y, Banks M, Sandor M, Fabry Z . In situ activation of antigen-specific CD8+ T cells in the presence of antigen in organotypic brain slices. J Immunol. 2008; 180(12):8393-9. PMC: 3338102. DOI: 10.4049/jimmunol.180.12.8393. View

16.

Ibeas Bih C, Chen T, Nunn A, Bazelot M, Dallas M, Whalley B . Molecular Targets of Cannabidiol in Neurological Disorders. Neurotherapeutics. 2015; 12(4):699-730. PMC: 4604182. DOI: 10.1007/s13311-015-0377-3. View

17.

Greenlee J . Treatment of paraneoplastic cerebellar degeneration. Curr Treat Options Neurol. 2013; 15(2):185-200. PMC: 7102346. DOI: 10.1007/s11940-012-0215-4. View

18.

Hwang J, Lee J, Oh C, Kang H, Hwang I, Um J . Proteolytic degradation and potential role of onconeural protein cdr2 in neurodegeneration. Cell Death Dis. 2016; 7(6):e2240. PMC: 5143381. DOI: 10.1038/cddis.2016.151. View

19.

Petitet F, Jeantaud B, Reibaud M, Imperato A, Dubroeucq M . Complex pharmacology of natural cannabinoids: evidence for partial agonist activity of delta9-tetrahydrocannabinol and antagonist activity of cannabidiol on rat brain cannabinoid receptors. Life Sci. 1998; 63(1):PL1-6. DOI: 10.1016/s0024-3205(98)00238-0. View

20.

Araujo I, Carreira B, Pereira T, Santos P, Soulet D, Inacio A . Changes in calcium dynamics following the reversal of the sodium-calcium exchanger have a key role in AMPA receptor-mediated neurodegeneration via calpain activation in hippocampal neurons. Cell Death Differ. 2007; 14(9):1635-46. DOI: 10.1038/sj.cdd.4402171. View