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 ?-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 ?-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 ?-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 ?- synuclein gene or a mutant human ?-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 ?-synuclein and determine the impact of pathologic ?-synuclein on bladder function. Our preliminary data indicate that ?-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 ?-synuclein mutation. These findings suggest an important role for ?-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 ?-synuclein. Therefore, in specific aim 2, we will determine the extent to which ?-synuclein-myosin Va protein interactions influence neurotransmission in the bladder. The interaction between myosin Va and ?-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 ?- synuclein in peripheral nerves; (2) determined whether local defects in neurotransmission contribute to bladder dysfunction in early stages of PD; (3) established the time course of these changes; (4) confirmed a role for ?- synuclein - myosin Va interactions in regulating synaptic vesicle trafficking; and (5) assessed how aberrant interactions impact neurotransmitter release. The next phase of the project will include a more detailed investigation of dysfunctional neurotransmission in the bladder during early PD and of ?- synuclein -myosin Va interactions that underlie those deficits. Findings from this project will ultimately advance our current understanding of the pathophysiology of neurogenic bladder dysfunction in PD and may provide the foundation for the design of better targeted pharmacotherapy for the neurogenic bladder.
Parkinson?s Disease is increasingly prevalent in the aging veteran population, particularly as service connected events continue to intensify the risk of developing this disease. The negative impact of Parkinson?s disease on the physical, mental, emotional and social health of the veteran population, as well as on the financial and healthcare delivery responsibilities of the VHA, underlie the critical need to better understand and manage this debilitating disease. We are proposing a novel paradigm of detrusor dysfunction that develops in the early stage of the disease in which locally mediated changes in bladder neurotransmission that precede the onset of somatomotor disorders progressively alter bladder function. A better understanding of neurogenic bladder dysfunction in patients with Parkinson?s disease may contribute to elucidating the complex mechanisms driving the neuropathology and provide an opportunity for early intervention.
