Synaptic Proteins, Trophic Factors and Neurodegeneration

描述(由申请人提供)：最基本的问题之一 与人类疾病中神经退行性变的进行性有关 神经元死亡。保护神经细胞免受形态衰退和死亡 需要阻断抑制神经修复的内在因素。在现在 提案，我们提供了一种创新的方法来研究这些因素 一种新的突触小鼠模型在帕金森病(PD)中的活跃作用 黑质纹状体丧失和不可逆转的变性。我们建议跟踪变化 一种关键的突触蛋白，a-突触核蛋白，在其自然环境中 突触前终末和神经毒性条件下，当它成为 不溶于水并累积。我们将进一步将这些更改与更改关联起来 神经营养支持。我们已经建立了一个动物方案，通过治疗C57/bl 小鼠以丙磺舒250 mg/kg和MPTP 250 mg/kg联合给药。 25 mg/kg，连续5周。这些小鼠表现出缓慢的、进行性的黑质纹状体的消失。 多巴胺能功能至少6个月，这模拟帕金森病，没有迹象表明 恢复。在药物治疗三周后， 黑质(SN)细胞的数量及其在 突触下α-突触蛋白免疫反应阳性终末的分布和密度。 这些变化可能预示着一系列事件的开始，这些事件导致 细胞死亡。在这项提案中，我们将重点关注 多巴胺能神经元在黑质及其传入，并呈现三种特异性 旨在通过一系列假设来解决。具体地说，我们计划 1)确定黑质突触的来源和神经化学表型。 含有α-突触核蛋白并确定MPTP丙磺舒治疗是否导致 2)在MPTP P模型中确定时间上的 细胞死亡与α-突触蛋白阳性突触之间的关系 多巴胺的功能和行为；以及3)确定a-突触核蛋白的变化 神经营养支持的改变促进了表达和产物的产生。这个 我们研究的总体目标是了解两者之间的关系 突触蛋白、α-突触核蛋白、神经营养支持，尤其是脑源性 神经营养因子及其在帕金森病中的作用 神经退行性变。这项研究的发现应该会对目标有所帮助。 可以实施神经保护策略的领域。

Description (Provided by applicant): One of the most fundamental questions related to the progressive nature of neurodegeneration in human disease is how neurons die. Protecting nerve cells against morphological decline and death requires blocking intrinsic factors that inhibit neural repair. In the present proposal, we offer an innovative approach to study those factors that are active in Parkinson's disease (PD) in a new mouse model that shows synaptic loss and irreversible nigrostriatal degeneration. We propose to track changes of a key synaptic protein, a-synuclein, both in its native environment at presynaptic terminals and under neurotoxic conditions, when it becomes insoluble and accumulates. We will further correlate those changes with altered neurotrophic support. We have established an animal protocol by treating C57/bl mice with a combined regimen of 10 doses of probenecid at 250mg/kg and MPTP at 25mg/kg for 5 weeks. These mice show a slow, progressive loss of nigrostriatal dopaminergic function for at least 6 months, that mimics PD, with no signs of recovery. Three weeks after drug treatment, there is a significant reduction in the number of substantia nigra (SN) cells and dramatic changes in the subsynaptic distribution and density of a-synuclein-immunoreactive terminals. These changes could signal the beginning of a chain of events that leads to cell death. In this proposal, we will focus on the progressive deterioration of dopaminergic neurons in the SN and their inputs, and present three specific aims to be addressed through a series of hypotheses. Specifically, we plan to 1) ascertain the origin and neurochemical phenotype of synapses in the SN that contain a-synuclein and to establish whether MPTP + probenecid treatment leads to their degeneration; 2) determine, in the MPTP+P model, the temporal relationships between cell death and a-synuclein-positive synapses, decline in dopamine function and behavior; and 3) ascertain whether changes in a-synuclein expression and production are precipitated by altered neurotrophic support. The overall objective of our research is to understand the relationship between the synaptic protein, a-synuclein, neurotrophic support, especially brain-derived neurotrophic factor (BDNF) and their respective roles in the PD form of neurodegeneration. The findings of this research should shed light on target areas where neuroprotection strategies can be implemented.