THE NEURONAL RNA-BINDING PROTEIN NOVA-2 IS IMPLICATED AS THE AUTOANTIGEN TARGETED IN POMA PATIENTS WITH DEMENTIA

Paraneoplastic opsoclonus myoclonus ataxia (POMA) is a neurologic diso rder 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 identif ied as a neuron-specific KH-type RNA-binding protein. Nova-1 expressio n is restricted to specific regions of the central nervous system, pri marily the hindbrain and ventral spinal cord, which correlate with the predominantly motor symptoms in POMA. However, POMA antisera recogniz e antigens that are widely expressed in both caudal and rostral region s of the central nervous system, and some patients develop cognitive s ymptoms, 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 i n adulthood, and at lower levels in the adult lung, In the postnatal m ouse brain, Nova-2 is expressed in a pattern that is largely reciproca l with Nova-1, including high levels of Nova-2 expression in the neoco rtex and hippocampus, Functional characterization of Nova-2 in RNA sel ection and nitrocellulose filter-binding assays reveals that Nova-2 bi nds 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-bind ing proteins. The expression pattern of the Nova-2 protein is likely t o underlie the development of cognitive deficits in some POMA patients .