Dysregulation of Neurotransmission in the Bladder with Parkinson's Disease

膀胱功能障碍在帕金森氏病(PD)患者中非常普遍，并经常使人虚弱。 进行性运动障碍的特征是各种疾病中出现异常聚集的α-突触核蛋白 大脑区域。下尿路症状(大小便失禁、尿急、夜尿等)帕金森病患者中 通常归因于大脑排尿中心中枢抑制的神经缺陷，导致 逼尿肌过度活动。然而，α-突触核蛋白病理对膀胱周围神经控制的直接影响 功能之前未被检查过。此外，最近的流行病学证据表明，非运动性 帕金森病患者出现运动障碍之前可能会出现症状。这些因素 促使我们重新检查帕金森病患者神经原性膀胱功能障碍的病理生理学，并解决 新的假说认为膀胱局部神经传递的外周调节显著改变 早期帕金森病，在运动障碍发作之前。我们的第一个目标是证明病理性α-突触核蛋白 帕金森病的表达导致膀胱神经传递和收缩功能的暂时性变化 躯体运动缺陷。我们将开发帕金森病的转基因动物模型，表达野生型人类α- 突触核蛋白基因或在家族性帕金森病中发现的突变型人类α-突触核蛋白基因。膀胱炎的表型 这些动物将通过体外和体内功能来综合表征年龄的增长。 化验。这些研究将使我们能够评估局部α-突触核蛋白的生理作用并确定其影响 病理性α-突触核蛋白对膀胱功能的影响。我们的初步数据表明α-突触核蛋白高度表达 在人类和小鼠膀胱内的神经纤维中，对神经刺激的功能反应是 α-突触核蛋白突变小鼠的膀胱发生了戏剧性的变化。这些发现表明一个重要的角色 对于突触小泡运输中的α-突触核蛋白，在一条由肌球蛋白Va共享的途径中，肌球蛋白Va是一种进行性马达蛋白 我们之前已经证明参与内脏器官的囊泡运输和神经传递。 我们的初步数据表明，肌球蛋白Va和α-突触核蛋白之间存在相关的分子内关系。 因此，在特定的目标2中，我们将确定α-突触核蛋白-肌球蛋白Va蛋白相互作用的程度 影响膀胱的神经传递。肌球蛋白Va和α-突触核蛋白之间的相互作用将被评估 在生理条件下使用分子和细胞方法在膀胱组织中进行研究。这种生理蛋白质- 蛋白质的相互作用将与PD和PD患者膀胱中的缺陷相互作用进行比较。 与分离的膀胱神经释放的神经递质水平的变化有关。在结束时 在这些研究中，我们将有：(1)对α-突触核蛋白的生理功能提供新的见解。 周围神经；(2)确定局部神经传递缺陷是否导致膀胱功能障碍 在PD的早期阶段；(3)确定了这些变化的时间进程；(4)确认了α-突触核蛋白的作用- 肌球蛋白Va在调节突触小泡运输中的相互作用；以及(5)评估异常相互作用如何 影响神经递质的释放。该项目的下一阶段将包括对 早期帕金森病患者膀胱的神经传递功能障碍以及α-突触核蛋白-肌球蛋白Va相互作用 这是这些赤字的根源。这个项目的发现将最终推动我们目前对 帕金森病神经源性膀胱功能障碍的病理生理机制及可能为更好的设计提供基础 神经源性膀胱的靶向药物治疗。

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 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 α- 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 α- 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.