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Nigrostriatal Damage Preferentially Decreases a Subpopulation of 62^* nAChRs in Mouse, Monkey, and Parkinson's Disease Striatum

The Parkinson's Institute, Sunnyvale, California (T.B., M.Q.); Institute for Behavioral Genetics, University of Colorado, Boulder, Colorado (S.R.G.); and Departments of Biology and Psychiatry, University of Utah, Salt Lake City, Utah (J.M.M.).

Parkinson's disease is a neurodegenerative movement disorder characterized by a loss of substantia nigra dopamine neurons, and corresponding declines in molecular components present on striatal dopaminergic nerve terminals. These include the 62^* nicotinic acetylcholine receptors (nAChRs), which are localized exclusively on dopamine terminals in striatum (^*denotes the presence of possible additional subunits). In this study, we used a novel -conotoxin MII (-CtxMII) analog E11A to further investigate 62^* nAChR subtypes in mouse, monkey, and human striatum. Receptor competition studies with ¹²⁵I--CtxMII showed that E11A inhibition curves were biphasic, suggesting the presence of two distinct 62^* nAChR subtypes. These include a very high (femtomolar) and a high (picomolar) affinity site, with 40% of the sites in the very high affinity form. It is noteworthy that only the high-affinity form was detected in 4 nAChR-null mutant mice. Because ¹²⁵I--CtxMII binds primarily to 6423 and 623 nAChR subtypes in mouse striatum, these data suggest that the population lost in the 4 knockout mice was the 6423 subtype. We next investigated the effect of nigrostriatal lesioning on these two striatal 62^* populations in two animal models and in Parkinson's disease. There was a preferential loss of the very high affinity subtype in striatum of mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), monkeys treated with MPTP, and patients with Parkinson's disease. These data suggest that dopaminergic terminals expressing the 6423 population are selectively vulnerable to nigrostriatal damage. This latter nAChR subtype, identified with -CtxMII E11A, may therefore provide a unique marker for dopaminergic terminals particularly sensitive to nigrostriatal degeneration in Parkinson's disease.

Address correspondence to: Dr. Maryka Quik, The Parkinson's Institute, 1170 Morse Ave, Sunnyvale, CA 94089-1605. E-mail: mquik{at}parkinsonsinstitute.org

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