Neuronal nicotinic receptor modulation and cerebellar ataxias

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DESCRIPTION (provided by applicant): There is no current pharmacological treatment to alleviate the imbalance and lack of voluntary muscle coordination manifest by individuals with ataxia. Ataxic movements affecting balance and coordination may be a consequence of either hereditary diseases or non-hereditary causes, and typically may be ascribed to a loss of function in the cerebellum or its associated afferent or efferent pathways. Although knowledge of the genetic basis of several cerebellar ataxias is increasing at a rapid pace and may lead to gene therapy approaches for treatment, this area is in its infancy. In addition, because many ataxias are a consequence of a cerebellar insult and do not involve genetic alterations, there is a need for the development of therapeutic agents to alleviate the symptoms associated with these disorders. Clinical studies have indicated that varenicline, a partial agonist at a4b2 and full agonist at a7 neuronal nicotinic receptors, improves balance and coordination in patients with ataxias of distinct pathogenic etiology, and recent preclinical studies in our laboratory have provided proof-of-principle that neuronal nicotinic receptor agonists prevent the progression of and/or improve motor behavior in an animal model of olivocerebellar degeneration. Based on these findings, the overall goal of this proposal is to further characterize the ability of neuronal nicotinic receptor agonists to alleviate ataxia in animal models and identify the cellular mechanisms involved. The overall hypothesis to be tested is that the partial activation of a4b2 and/or full activation of a7 neuronal nicotinic receptors in the cerebellum or inferior olive leads to the increased expression and release of insulin-like growth factor (IGF-1) in the cellular milieu, which shifts the balance between pro-apoptotic and anti-apoptotic signaling to favor the latter. Through a complementary and parallel series of in vivo and in vitro studies involving both diverse animal models and tissue and cell-based assays, this translational proposal will use a classical pharmacological approach to identify the specific receptor subtypes mediating the anti-ataxic effects of neuronal nicotinic receptor agonists and determine whether these compounds can alleviate ataxias resulting from different chemical and genetic insults. Further, through measures of key molecules involved in apoptotic signaling, studies will ascertain whether nicotinic receptor agonists promote cell survival, and whether this action is a consequence of a nicotinic receptor-mediated increased expression of IGF-1. Results will lead to the development of new therapeutic agents for the treatment of these disorders for which there is no current efficacious pharmacological therapy. PUBLIC HEALTH RELEVANCE: Currently, there is no pharmacological treatment to alleviate the imbalance and lack of voluntary muscle coordination manifest by individuals with ataxia. Ataxic movements affecting balance and coordination may be a consequence of either hereditary diseases or non-hereditary causes, and typically may be ascribed to a loss of function in the cerebellum or its associated afferent or efferent pathways. Recent clinical studies have indicated that varenicline, a partial agonist at a4b2 and full agonist at a7 neuronal nicotinic receptors, improves balance and coordination in patients with ataxia of distinct pathogenic etiology, and preclinical studies have provided proof-of-principle for the use of nicotinic agonists in ataxia, but the mechanism(s) involved have not been elucidated. This proposal will investigate key molecules that may be involved in mediating the ability of nicotinic agonists to improve ataxia. Results will lead to the development of new therapeutic agents for the treatment of these disorders for which there is no current efficacious pharmacological therapy.