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Paraneoplastic CDR2 and CDR2L antibodies affect Purkinje cell calcium homeostasis
Manja Schubert1, Debabrata Panja, Mette Haugen
1Department of Neurology, Haukeland University Hospital, 5021, Bergen, Norway, schubert_manja@hotmail.com.
Abstract:
Paraneoplastic cerebellar degeneration (PCD) is characterized by loss of Purkinje cells (PCs) associated with progressive pancerebellar dysfunction in the presence of onconeural Yo antibodies. These antibodies recognize the cerebellar degeneration-related antigens CDR2 and CDR2L. Response to PCD therapy is disappointing due to limited understanding of the neuropathological mechanisms. Here, we report the pathological role of CDR antibodies on the calcium homeostasis in PCs. We developed an antibody-mediated PCD model based on co-incubation of cerebellar organotypic slice culture with human patient serum or rabbit CDR2 and CDR2L antibodies. The CDR antibody-induced pathology was investigated by high-resolution multiphoton imaging and biochemical analysis. Both human and rabbit CDR antibodies were rapidly internalized by PCs and led to reduced immunoreactivity of calbindin D28K (CB) and L7/Pcp-2 as well as reduced dendritic arborizations in the remaining PCs. Washout of the CDR antibodies partially recovered CB immunoreactivity, suggesting a transient structural change in CB calcium-binding site. We discovered that CDR2 and CB co-immunoprecipitate. Furthermore, the expression levels of voltage-gated calcium channel Cav2.1, protein kinase C gamma and calcium-dependent protease, calpain-2, were increased after CDR antibody internalization. Inhibition of these signaling pathways prevented or attenuated CDR antibody-induced CB and L7/Pcp-2 immunoreactivity loss, morphological changes and increased protein expression. These results signify that CDR antibody internalization causes dysregulation of cell calcium homeostasis. Hence, drugs that modulate these events may represent novel neuroprotective therapies that limit the damaging effects of CDR antibodies and prevent PC neurodegeneration.
Insights
Paraneoplastic cerebellar degeneration (PCD) involves Yo antibodies attacking Purkinje cells (PCs). This study reveals these antibodies disrupt PC calcium homeostasis, offering new therapeutic targets for neuroprotection.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Paraneoplastic cerebellar degeneration (PCD) is a severe neurological disorder characterized by Purkinje cell (PC) loss and progressive pancerebellar dysfunction.
- The condition is strongly associated with onconeural Yo antibodies, which target cerebellar degeneration-related autoantigens CDR2 and CDR2L.
- Current therapeutic strategies for PCD yield limited success, underscoring the need for a deeper understanding of its underlying neuropathological mechanisms.
Purpose of the Study:
- To investigate the pathological role of CDR antibodies in Purkinje cell (PC) calcium homeostasis.
- To elucidate the molecular mechanisms by which CDR antibodies induce neurodegeneration in the cerebellum.
- To identify potential therapeutic targets for mitigating CDR antibody-induced neurotoxicity.
Main Methods:
- Development of an antibody-mediated PCD model using cerebellar organotypic slice cultures incubated with patient serum or rabbit anti-CDR2/CDR2L antibodies.
- High-resolution multiphoton imaging and biochemical analyses to assess PC morphology, protein expression, and calcium homeostasis.
- Co-immunoprecipitation assays to identify interactions between CDR2 and calbindin D28K (CB).
Main Results:
- Internalization of CDR antibodies by PCs led to reduced calbindin D28K (CB) and L7/Pcp-2 immunoreactivity and dendritic arborization.
- CDR2 was found to co-immunoprecipitate with CB, indicating a direct interaction.
- Increased expression of Cav2.1, protein kinase C gamma, and calpain-2 was observed following CDR antibody internalization.
- Inhibition of specific signaling pathways ameliorated CDR antibody-induced damage, suggesting a role in calcium dysregulation.
Conclusions:
- CDR antibody internalization disrupts Purkinje cell calcium homeostasis, contributing to neurodegeneration in PCD.
- The findings highlight the critical role of CDR2-CB interaction and downstream signaling pathways in PCD pathogenesis.
- Modulating these calcium-related pathways presents a promising avenue for novel neuroprotective therapies against PCD.
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