High-throughput screening assay development for axonopathic neurodegeration

描述（由申请人提供）：许多神经退行性疾病，如阿尔茨海默病、多发性硬化症和肌萎缩性侧索硬化症（ALS），会导致神经元轴突的不可逆破坏。一旦轴突被破坏，神经元的信号传导机制就不复存在，因此大脑容量急剧下降。众所周知，轴突的退化是一个由神经元自身控制的活跃过程。此外，已知如果蛋白质和细胞器沿轴突的运输被减慢，轴突自我破坏的过程就会被刺激。关于控制轴突变性及其与轴突运输中断的联系的确切机制知之甚少。然而，有很好的轴突运输标记，可以用来表征轴突运输相关的变性。其中一个标记是淀粉样前体蛋白（APP），在神经变性病理标本的轴突聚集物中发现。本提案旨在设计高通量筛选，以发现轴突运输的遗传修饰剂和app相关轴突变性的药物化合物修饰剂。因此，这项工作的长期目标是更好地了解神经退行性疾病中轴突破坏的原因，并找到可以减缓或防止轴突变性发生的药物。

DESCRIPTION (provided by applicant): Many neurodegenerative diseases, such as Alzheimer's disease, multiple sclerosis, and amyotrophic lateral sclerosis (ALS), lead to the irreversible destruction of neuronal axons. Once axons are destroyed, there is no mechanism left for neuronal signaling, thus a drastic reduction of brain capacity occurs. It is known that the degeneration of axons is an active process that is controlled by the neuron itself. In addition, it is known that if transport of proteins and organelles along axons is slowed, this process of axonal self-destruction is stimulated. Very little is known about the exact mechanisms that control axonal degeneration and its link to disrupted axon transport. However there are excellent markers of axon transport that can be used to characterize axon transport-associated degeneration. One of these markers is amyloid precursor protein (APP), which is found in axonal aggregates from neurodegeneration pathology specimens. This proposal seeks to design high-throughput screens that will find genetic modifiers of axon transport, and drug compound modifiers of APP-associated axonal degeneration. The long term goal of this work is thus to understand better the causes of axonal destruction in neurodegenerative diseases, and to find drugs that can slow or prevent axonal degeneration from occurring.