Bladder Dysfunction and Dysregulation of Neurotransmission

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Bladder dysfunction is a common, distressing finding in patients afflicted with two disorders that are increasingly prevalent in the general population but significantly over- represented in the veteran population—type 2 diabetes (T2DM) and Parkinson’s disease (PD). Currently, treatments for bladder dysfunction address the symptoms, not the cause, which remains largely unknown. Though bladder dysfunction manifests early in the course of each disease, it frequently remains unrecognized and worsens with disease progression. T2DM and PD can occur independently, however these disorders are related and sometimes coincident. It has been shown that T2DM increases the risk of PD, and PD patients with T2DM develop more aggressive motor and cognitive impairment. Such reciprocity is likely to spring from a common biochemical mechanism underlying the pathogenesis of both chronic diseases, with adverse consequences for bladder function. The pathology of PD is associated with aggregation of alpha synuclein (αSyn), a protein abundant in presynaptic nerve varicosities whose biological function, though incompletely understood, encompasses a role in facilitation of neurotransmission. In this proposal, we present and rigorously test our proposed mechanism of αSyn interaction with the unconventional motor protein, myosin 5a (Myo5a), as well as with cytoskeletal actin, in functional processes involving neurotransmission and glucose regulation in the bladder. We will examine perturbation of this mechanism in both T2DM and PD animal models and under in vitro hyperglycemic conditions. We also propose to investigate the influence of glucagon-like peptide agonists, agents used in T2DM treatment, on restoring the αSyn-Myo5a-actin axis. The multidisciplinary studies proposed herein will integrate biochemical, molecular, cellular and physiological approaches that exploit state of the art methods combined with proven conventional techniques. The information gained will provide a foundation for more effective interventions addressing the foundational causes of bladder dysfunction and deficits in bladder neurotransmission in patients with T2DM and PD.