Bladder dysfunction is highly prevalent and often debilitating in patients with Parkinson’s disease (PD), a progressive movement disorder characterized by the appearance of abnormal aggregated α-synuclein in various brain regions. Lower urinary tract symptoms (incontinence, urgency, nocturia, etc.) in patients with PD are generally attributed to neurologic defects in the central inhibition of micturition centers in the brain that result in detrusor overactivity. However, a direct effect of α-synuclein pathology on peripheral neural control of bladder function has not been previously examined. Moreover, recent epidemiological evidence suggests that non-motor symptoms may substantially precede the development of movement disorders in patients with PD. These factors have prompted us to re-examine the pathophysiology of neurogenic bladder dysfunction in PD and address the novel hypothesis that peripheral regulation of local neurotransmission in the bladder is significantly altered in early stage PD, prior to the onset of motor deficits. Our first aim will be to demonstrate that pathologic α-synuclein expression in PD causes temporal changes in bladder neurotransmission and contractile function that precede somatomotor deficits. We will exploit transgenic animal models of PD that express either the wild-type human α- synuclein gene or a mutant human α-synuclein gene found in a form of familial PD. The bladder phenotype of these animals will be comprehensively characterized at increasing ages using in vitro and in vivo functional assays. These studies will allow us to assess the physiologic role of local α-synuclein and determine the impact of pathologic α-synuclein on bladder function. Our preliminary data indicate that α-synuclein is highly expressed in human and mouse nerve fibers within the bladder and that the functional response to nerve stimulation is dramatically altered in bladders from mice with α-synuclein mutation. These findings suggest an important role for α-synuclein in synaptic vesicle transport, in a pathway that is shared by myosin Va, a processive motor protein that we have previously shown to be involved in vesicular trafficking and neurotransmission in visceral organs. Our preliminary data suggests a relevant intramolecular relationship between myosin Va and α-synuclein. Therefore, in specific aim 2, we will determine the extent to which α-synuclein-myosin Va protein interactions influence neurotransmission in the bladder. The interaction between myosin Va and α-synuclein will be assessed in bladder tissue under physiologic conditions using molecular and cellular approaches. This physiologic protein- protein interaction will be compared with the defective interaction in the bladder that occurs with PD and correlated with changes in the level of neurotransmitters released from isolated bladder nerves. At the conclusion of these studies, we will have: (1) provided new insights regarding the physiologic function of α- synuclein in pe...