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The neuronal RNA-binding protein Nova-2 is implicated as the autoantigen targeted in POMA patients with dementia
Y Y Yang1, G L Yin, R B Darnell
1Laboratory of Molecular Neuro-Oncology, The Rockefeller University, New York, NY 10021, USA.
Abstract:
Paraneoplastic opsoclonus myoclonus ataxia (POMA) is a neurologic disorder thought to be mediated by an autoimmune attack against onconeural disease antigens that are expressed by gynecologic or lung tumors and by neurons. One POMA disease antigen, termed Nova-1, has been identified as a neuron-specific KH-type RNA-binding protein. Nova-1 expression is restricted to specific regions of the central nervous system, primarily the hindbrain and ventral spinal cord, which correlate with the predominantly motor symptoms in POMA. However, POMA antisera recognize antigens that are widely expressed in both caudal and rostral regions of the central nervous system, and some patients develop cognitive symptoms. We have used POMA antisera to clone a cDNA encoding a second POMA disease antigen termed Nova-2. Nova-2 is closely related to Nova-1, and is expressed at high levels in neurons during development and in adulthood, and at lower levels in the adult lung. In the postnatal mouse brain, Nova-2 is expressed in a pattern that is largely reciprocal with Nova-1, including high levels of Nova-2 expression in the neocortex and hippocampus. Functional characterization of Nova-2 in RNA selection and nitrocellulose filter-binding assays reveals that Nova-2 binds RNA with high affinity and with sequence specificity that differs from Nova-1. Our results demonstrate that the immune response in POMA targets a family of highly related sequence-specific neuronal RNA-binding proteins. The expression pattern of the Nova-2 protein is likely to underlie the development of cognitive deficits in some POMA patients.
Insights
Paraneoplastic opsoclonus myoclonus ataxia (POMA) involves an autoimmune response targeting neuronal proteins. Researchers identified Nova-2, a new antigen, which may explain cognitive symptoms in POMA patients.
Area of Science:
- Neuroimmunology
- Molecular Biology
- Oncology
Background:
- Paraneoplastic opsoclonus myoclonus ataxia (POMA) is a neurological disorder linked to autoimmune responses against neuronal antigens.
- Nova-1, a neuron-specific RNA-binding protein, is a known POMA antigen, but its expression pattern doesn't fully explain all POMA symptoms.
- Some POMA patients exhibit cognitive deficits, suggesting involvement of additional antigens with broader expression patterns.
Purpose of the Study:
- To identify and characterize a second POMA disease antigen.
- To investigate the expression pattern and function of the newly identified antigen.
- To correlate antigen expression with the diverse clinical manifestations of POMA.
Main Methods:
- Utilized POMA patient antisera to clone a cDNA encoding a novel antigen, Nova-2.
- Analyzed Nova-2 expression in various tissues and developmental stages using molecular techniques.
- Performed RNA binding assays to determine Nova-2's functional properties and sequence specificity.
Main Results:
- Identified and cloned Nova-2, a protein closely related to Nova-1.
- Nova-2 is expressed in neurons throughout development and adulthood, with distinct regional specificity compared to Nova-1.
- Nova-2 binds RNA with high affinity and sequence specificity, differing from Nova-1.
- Nova-2 is also expressed in the adult lung at lower levels.
Conclusions:
- The immune response in POMA targets a family of related, sequence-specific neuronal RNA-binding proteins.
- Nova-2's expression pattern, particularly in the neocortex and hippocampus, likely contributes to cognitive deficits observed in some POMA patients.
- Understanding Nova-2's role provides insights into the pathogenesis of POMA and its varied clinical presentations.