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The onconeural antigen Nova-1 is a neuron-specific RNA-binding protein, the activity of which is inhibited by
R J Buckanovich1, Y Y Yang, R B Darnell
1Laboratory of Molecular Neuro-Oncology, Rockefeller University, New York, New York 10021, USA.
Abstract:
Nova-1, a protein expressed in tumors and neurons, is a target antigen in a human paraneoplastic motor disorder [paraneoplastic opsoclonus-myoclonus ataxia (POMA)]. We evaluated the relationship between the function of Nova-1 and its role as a disease antigen. We show that Nova-1 is a neuron-specific RNA-binding protein with sequence and functional similarities to FMR-1. Nova-1 mRNA is restricted to the subcortical nervous system, and the protein binds to RNA with high affinity. Nova-1 KH domains mediate this RNA binding, and point mutations within them abrogate binding. POMA disease antisera (6/6) recognize the third KH domain but not an inactive point mutant, and affinity-purified antibody blocks Nova-1 RNA binding. Thus, a cardinal feature of POMA is the production of antibodies that inhibit Nova-1-RNA interactions, suggesting such inhibition may cause the neurological disease.
Insights
Nova-1 protein is crucial for nervous system function and is targeted in paraneoplastic opsoclonus-myoclonus ataxia (POMA). Antibodies in POMA patients inhibit Nova-1
Area of Science:
- Neuroscience
- Immunology
- Molecular Biology
Background:
- Nova-1 is a protein found in tumors and neurons, identified as a target antigen in paraneoplastic opsoclonus-myoclonus ataxia (POMA).
- Understanding Nova-1's function and its role in POMA is critical for elucidating the disease's pathogenesis.
Purpose of the Study:
- To investigate the functional relationship between Nova-1 and its involvement as a disease antigen in POMA.
- To determine how Nova-1's RNA-binding activity is affected by the immune response in POMA.
Main Methods:
- Characterization of Nova-1 as a neuron-specific RNA-binding protein.
- Analysis of Nova-1 mRNA distribution within the nervous system.
- Investigation of Nova-1's RNA-binding domains (KH domains) and the impact of mutations.
- Testing POMA patient antibodies against Nova-1 and its mutants, and assessing antibody-mediated inhibition of RNA binding.
Main Results:
- Nova-1 is a neuron-specific RNA-binding protein, similar in sequence and function to FMR-1, with mRNA localized to the subcortical nervous system.
- Nova-1 binds RNA with high affinity via its KH domains; mutations in these domains abolish RNA binding.
- All tested POMA patient antisera recognized the third KH domain of Nova-1 and inhibited Nova-1's RNA binding.
Conclusions:
- A key characteristic of POMA is the generation of antibodies that specifically inhibit Nova-1's RNA-binding activity.
- This antibody-mediated inhibition of Nova-1-RNA interactions is a potential cause of the neurological dysfunction observed in POMA.