Nigrostriatal damage preferentially decreases a subpopulation of α6β2*nAChRs in mouse, monkey, and Parkinson's disease striatum

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 alpha 6 beta 2* 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 alpha-conotoxin MII (alpha-CtxMII) analog E11A to further investigate alpha 6 beta 2* nAChR subtypes in mouse, monkey, and human striatum. Receptor competition studies with I-125-alpha-CtxMII showed that E11A inhibition curves were biphasic, suggesting the presence of two distinct alpha 6 beta 2* nAChR subtypes. These include a very high (femtomolar) and a high (picomolar) affinity site, with similar to 40% of the sites in the very high affinity form. It is noteworthy that only the high-affinity form was detected in alpha 4 nAChR-null mutant mice. Because I-125-alpha-CtxMII binds primarily to alpha 6 alpha 4 beta 2 beta 3 and alpha 6 beta 2 beta 3 nAChR subtypes in mouse striatum, these data suggest that the population lost in the alpha 4 knockout mice was the alpha 6 alpha 4 beta 2 beta 3 subtype. We next investigated the effect of nigrostriatal lesioning on these two striatal alpha 6 beta 2* 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-4phenyl-1,2,3,6- tetrahydropyridine (MPTP), monkeys treated with MPTP, and patients with Parkinson's disease. These data suggest that dopaminergic terminals expressing the alpha 6 alpha 4 beta 2 beta 3 population are selectively vulnerable to nigrostriatal damage. This latter nAChR subtype, identified with alpha-CtxMII E11A, may therefore provide a unique marker for dopaminergic terminals particularly sensitive to nigrostriatal degeneration in Parkinson's disease.