Novel Genetic Approaches to Evaluate Dominant Gain of Function Toxicity in Polygl

描述（由申请人提供）：聚谷氨酰胺（polyQ）扩增疾病是一种迟发性疾病，通过已显示的聚谷氨酰胺延伸毒性引起神经变性。在脊髓小脑共济失调或SCA中，这些影响了美国成千上万的患者，预后很差。随着这些共济失调的进展数年，甚至数十年的健康负担和痛苦的经验，那些受影响的是显着的。尽管知道致病因素和这些扩展的谷氨酰胺所在的基因，但了解这些有毒蛋白质的作用机制仍然不清楚，并且是一个激烈争论的问题。一些人认为核包容和核进口很重要。其他人则认为，细胞质堵塞阻碍了必要货物的通过。即使是引起毒性的是基于RNA的机制还是基于蛋白质的机制的问题也存在强烈争议（在Orr，HT 2012中综述）。最近，它被观察到在果蝇求偶电路的SCA片段的表达，包含在其多聚谷氨酰胺残基的扩展导致行为异常。这种异常可能是早期神经元丢失或衰退的结果。由于这种求偶回路中的死亡或功能障碍会导致交配能力下降，因此将其用作恢复行为筛选的基础。在追求的目标，以确定抑制行为异常的求爱，这个研究小组将追求两个目标。第一个目标是确定导致异常求偶的机制，确定它是基于细胞死亡还是基于细胞功能障碍，以及活动是否可以改变其敏感性。第二个目的是从polyQ诱导的交配能力下降中开发筛选，以便开发行为抑制因子的交配筛选。发展行为筛选技术带来的一个令人兴奋的前景是，它可能会识别出在毒性过程早期起作用的抑制因子。Orr HT脊髓小脑共济失调的细胞生物学J Cell Biol. Apr 16 2012;197（2）：167-177.

DESCRIPTION (provided by applicant): Polyglutamine (polyQ) expansion diseases are late-onset disorders that cause neurodegeneration through what has been shown to be toxicity of the polyglutamine stretch. In Spinocerebellar Ataxia, or SCAs, these affect thousands of patients in the U.S. and the prognosis is poor. As these ataxias progress for years-even decades-the health burden and suffering experienced by those affected are significant. Despite knowing the causative factor and the genes in which these expanded glutamines reside, understanding the mechanism of action for these toxic proteins is still unclear and a matter of intense debate. Some have argued nuclear inclusion and nuclear import are important. Others argue there is cytoplasmic clogging that is blocking the passage of necessary cargo. Even the issue of whether it is an RNA-based mechanism or a protein-based mechanism that causes toxicity is strongly debated (reviewed in Orr, HT 2012). Recently, it was observed in a Drosophila courtship circuit that expression of a SCA fragment containing an expansion in its polyglutamine residues led to behavioral anomalies. This anomaly might be the result of early neuronal loss or decay. Because death or dysfunction in this courtship circuit led to decreases in mating ability, its use as the basis for a behavioral screen for recovery presented itself. In pursuit of the goal to identify suppressors of behavioral anomalies in courtship, this research group will pursue two aims. The first aim is to identify the mechanism leading to aberrant courtship, determine whether it is cell death-based or cellular dysfunction-based, and whether activity can alter its sensitivity. The second aim is to develop a screen from polyQ-induced declines in mating ability in order to develop a mating screen for suppressors of a behavior. An exciting prospect brought about by developing a behavioral screen is the possibility that it might identify suppressors that act very early in the toxic process. Orr HT Cell biology of spinocerebellar ataxia J Cell Biol. Apr 16 2012;197(2):167---177.