The neuronal RNA-binding protein Nova-2 is implicated as the autoantigen targeted in POMA patients with dementia
Open accessAbstract
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.
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Aberrant alternative splicing has been implicated in many neurological diseases.
“Aberrant alternative splicing has been implicated in many neurological diseases (Buckanovich et al., 1996;Yang et al., 1998), yet the complex landscape of differential splicing among glia, neurons, and vascular cells has not been investigated.”
From An RNA-Sequencing Transcriptome and Splicing Database of Glia, Neurons, and Vascular Cells of the Cerebral Cortex (2014) · cites this paper as Yang et al., 1998
The Results (page not specified) mention possible alternatively spliced Nova-2 transcripts, while the Abstract links Nova-2 to the neurological disorder POMA. Neither passage says that the splicing is aberrant or implicates aberrant alternative splicing in neurological disease. A search for splicing found no passage establishing the claimed connection. (LLM, conf=0.76)
Experimental — accuracy not yet measuredDisruption of alternative splicing can lead to neurological diseases in human and animal models.
“previous studies have shown that disruption of alternative splicing can lead to neurological diseases in human and animal models (Buckanovich et al., 1996;Yang et al., 1998;Gehman et al., 2011)”
From An RNA-Sequencing Transcriptome and Splicing Database of Glia, Neurons, and Vascular Cells of the Cerebral Cortex (2014) · cites this paper as Yang et al., 1998
The Results describe a potential alternatively spliced Nova-2 transcript in mouse brain, while the Discussion links neurological dysfunction in POMA patients to immunologic targeting of Nova proteins. Neither passage says that disruption of alternative splicing causes neurological disease in humans or animal models; searches for that connection found no such passage. (LLM, conf=0.72)
Experimental — accuracy not yet measuredNova1−/− mice appear normal at birth but die in the second postnatal week with motor neuron apoptosis, profound motor failure and action-induced tremors.
“Nova1−/− mice appear normal at birth, but die in the second postnatal week with motor neuron apoptosis, profound motor failure and action-induced tremors37,38.”
From The neurogenetics of alternative splicing (2016) · cites this paper as [37]
NOVA1 is mainly expressed in the hindbrain and ventral spinal cord, whereas NOVA2 is predominant in the forebrain and dorsal spinal cord.
“NOVA1 is mainly expressed in the hindbrain and ventral spinal cord, whereas NOVA2 is predominant in the forebrain and dorsal spinal cord, with some overlapping expression in portions of the midbrain and hindbrain37.”
From The neurogenetics of alternative splicing (2016) · cites this paper as [37]
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- Authors
- Yang, Y. Y. L., Yin, G. L., & Darnell, R. B.
- Affiliations
- Rockefeller University (US)
- Yale University (US)
- ORCID
- Darnell, Robert B.
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 1998-10-27
- Volume
- 95
- Issue
- 22
- Pages
- 13254-13259
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC23773
- OpenAlex
- W1975958907
- Cited by
- 219
- References
- 36
- Citations by year
- 2026: 5 · 2025: 5 · 2024: 7 · 2023: 6 · 2022: 11 · 2021: 9 · 2020: 8 · 2019: 8 · 2018: 8 · 2017: 10 · 2016: 7 · 2015: 5 · 2014: 11 · 2013: 11 · 2012: 7
- FWCI
- 5.33
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Defense
- National Institutes of Health (NS34389)
- National Cancer Institute (CA 09673-18, T32CA009673)
- National Institute of General Medical Sciences (T32GM007739)
- National Institute of Neurological Disorders and Stroke (R01NS034389)
- Topics
- Health Sciences › Medicine › Neurology › Autoimmune Neurological Disorders and Treatments
- Health Sciences › Medicine › Neurology › Peripheral Neuropathies and Disorders
- Health Sciences › Medicine › Rheumatology › Systemic Lupus Erythematosus Research
- Keywords
- autoantigens, RNA binding specificity, cognitive impairment, dementia, onconeural antigens, autoimmune neurodegeneration, hippocampus, neocortex
- MeSH terms
- Neuro-Oncological Ventral Antigen, Amino Acid Sequence, Animals, Animals, Newborn, Antigens, Neoplasm, Autoantigens, Base Sequence, Binding Sites, Brain, Dementia, Humans, Molecular Sequence Data, Nerve Tissue Proteins, Oligoribonucleotides, Paraneoplastic Syndromes, Ribonucleoproteins, Ocular Motility Disorders, Sequence Alignment, RNA-Binding Proteins, Sequence Homology, Amino Acid, Gene Expression Regulation, Developmental, Mice
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