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Updated: Dec 7, 2025
Cerebellar Regional Dissection for Molecular Analysis
Published on: December 5, 2020
Localization of CDR2L and CDR2 in paraneoplastic cerebellar degeneration
Ida Herdlevaer1,2, Torbjørn Kråkenes1, Manja Schubert2
1Department of Clinical Medicine, University of Bergen, Bergen, Norway.
Objective:
Identify the subcellular location and potential binding partners of two cerebellar degeneration-related proteins, CDR2L and CDR2, associated with anti-Yo-mediated paraneoplastic cerebellar degeneration.
Methods:
Cancer cells, rat Purkinje neuron cultures, and human cerebellar sections were exposed to cerebrospinal fluid and serum from patients with paraneoplastic cerebellar degeneration with Yo antibodies and with several antibodies against CDR2L and CDR2. We used mass spectrometry-based proteomics, super-resolution microscopy, proximity ligation assay, and co-immunoprecipitation to verify the antibodies and to identify potential binding partners.
Results:
We confirmed the CDR2L specificity of Yo antibodies by mass spectrometry-based proteomics and found that CDR2L localized to the cytoplasm and CDR2 to the nucleus. CDR2L co-localized with the 40S ribosomal protein S6, while CDR2 co-localized with the nuclear speckle proteins SON, eukaryotic initiation factor 4A-III, and serine/arginine-rich splicing factor 2.
Interpretation:
We showed that Yo antibodies specifically bind to CDR2L in Purkinje neurons of PCD patients where they potentially interfere with the function of the ribosomal machinery resulting in disrupted mRNA translation and/or protein synthesis. Our findings demonstrating that CDR2L interacts with ribosomal proteins and CDR2 with nuclear speckle proteins is an important step toward understanding PCD pathogenesis.
Insights
Anti-Yo antibodies target CDR2L in the cytoplasm of Purkinje neurons, potentially disrupting protein synthesis in paraneoplastic cerebellar degeneration (PCD). CDR2 localizes to the nucleus, interacting with splicing factors.
Area of Science:
- Neuroimmunology
- Molecular Neuroscience
- Cell Biology
Background:
- Paraneoplastic cerebellar degeneration (PCD) with anti-Yo antibodies is a severe autoimmune neurological disorder.
- Cerebellar degeneration-related proteins CDR2L and CDR2 are implicated in anti-Yo PCD pathogenesis.
- Understanding the precise roles and interactions of CDR2L and CDR2 is crucial for elucidating PCD mechanisms.
Purpose of the Study:
- To determine the subcellular localization of CDR2L and CDR2.
- To identify binding partners of CDR2L and CDR2.
- To investigate the functional consequences of anti-Yo antibody binding to these proteins in PCD.
Main Methods:
- Mass spectrometry-based proteomics to confirm antibody specificity and identify binding partners.
- Super-resolution microscopy and proximity ligation assay for subcellular localization studies.
- Co-immunoprecipitation to validate protein-protein interactions.
Main Results:
- Yo antibodies specifically recognize CDR2L, which is localized to the cytoplasm.
- CDR2L was found to co-localize with the 40S ribosomal protein S6.
- CDR2 was localized to the nucleus and co-localized with nuclear speckle proteins SON, EIF4A3, and Srsf2.
Conclusions:
- Anti-Yo antibodies binding to CDR2L in Purkinje neurons may disrupt ribosomal function and protein synthesis, contributing to PCD.
- The interaction of CDR2L with ribosomal proteins and CDR2 with nuclear speckle proteins provides insights into PCD pathogenesis.
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