CDR2L (cerebellar degeneration-related protein 2-like) is a cytoplasmic protein primarily expressed in Purkinje cells and large brainstem neurons 1. It localizes to the cytoplasm and associates with the 40S ribosomal protein S6, suggesting a role in translation and protein synthesis 2. CDR2L also functions as an endoplasmic reticulum (ER) adaptor for cytoplasmic dynein-1, recruited by kinectin (KTN1) to regulate ER sheet organization and clustering near centrosomes 3. This dynein-binding function occurs through its CC1 box motif and involves competition with translation elongation factor eEF1Bβ for KTN1 binding 3. Clinically, CDR2L is the major target antigen of anti-Yo (PCA-1) autoantibodies in paraneoplastic cerebellar degeneration (PCD), a cancer-associated autoimmune disorder predominantly affecting women with gynecologic or breast adenocarcinoma 14. Anti-CDR2L antibodies are rapidly internalized by Purkinje cells, disrupting calcium homeostasis through altered expression of calbindin, voltage-gated calcium channels, and calcium-dependent proteases, ultimately leading to dendritic degeneration 5. Diagnostic testing using CDR2L alongside CDR2 significantly improves detection accuracy, with combined serum positivity achieving 100% sensitivity and 99.9% specificity for PCD 4. CDR2L-specific testing is particularly valuable in cerebrospinal fluid analysis, where it demonstrates superior sensitivity compared to CDR2 alone 6.