Disease-Modifying Genes in Huntington's Disease

亨廷顿病中的疾病修饰基因：HD是一种破坏性的神经退行性疾病， 在临床诊断后约15年，花费昂贵，使人衰弱的过程导致过早死亡。迫切需要有效的 治疗，以减轻痛苦和成本的个人，家庭和社会。HTT中的HD突变是一种 扩增的CAG三核苷酸重复序列，其长度是决定临床发作时间的主要因素。 尽管人们通常认为亨廷顿蛋白中多聚谷氨酰胺的长度决定了导致疾病的发病率， 到HD发作时，我们来自HD受试者的数据并不支持这一结论。疾病相关HTT等位基因， 相同的纯CAG重复序列大小可以产生不同大小的多聚谷氨酰胺束，这是由于可变的谷氨酰胺编码 CAA密码子，由于额外的谷氨酰胺，HD发作没有相应的加速。相反， 最好用纯CAG重复序列与其编码潜力分开的性质来解释。我们发现 HD发病年龄由6个基因座的遗传变异改变，这些基因座编码参与多种DNA的基因。 维护过程。在人类和小鼠模型中，这些遗传修饰剂涉及体细胞 CAG重复序列的扩增而不是编码的多聚谷氨酰胺作为决定发病年龄的因素。通过 相反，症状进展最多与CAG重复次数呈弱相关，而持续时间 显性疾病（即，从运动诊断到死亡的时间）与CAG重复序列长度无关，提示 从发病到死亡，其他因素在确定发病机制方面至关重要。总的来说，我们的研究结果表明， HD包括两个不同的组分：1）CAG重复序列的长度依赖性体细胞扩增， 超过阈值长度（速率驱动器），然后涉及毒性和2）尚未确定的机制， 当达到阈值长度时，体细胞扩增的重复序列触发损伤（毒性驱动）。的 毒性驱动因素的性质尚不明确。阈上多聚谷氨酰胺对亨廷顿蛋白的影响 （而不是持续的长度依赖性毒性）既有吸引力，又与长CAG的作用一致。 重复，但在转录或RNA水平上起作用的其他机制也被发现。 被认为是因果关系。我们人类基因战略的成功已经开始为人类提供新的目标， 延迟或预防HD发作的治疗干预。在这次更新中，我们将确定额外的费率调整因素 更全面地描述人体CAG扩增的过程，并将扩展我们的策略， 明显疾病的修饰物，其涉及毒性驱动剂的性质或其破坏性后果。的 新靶点的识别，与HD受试者中正在进行的生物学过程的自然变异有关 它们本身将为开发推动这些过程的药物干预提供坚实的基础 甚至更远，朝向强大的治疗益处。因此，这笔赠款的承诺是一个新的和强大的途径， 满足预显和显症HD受试者及其家属的最大需求：有效治疗 以阻断或延迟疾病的发作和进展。

Disease-Modifying Genes in Huntington's Disease: HD is a devastating neurodegenerative disorder with a long, costly, debilitating course to premature death, ~15 yrs after clinical diagnosis. There is a dire need for effective therapies to alleviate the suffering and cost to the individual, family and society. The HD mutation in HTT is an expanded CAG trinucleotide repeat whose length is the main factor determining the timing of clinical onset. Although it is often assumed that the length of polyglutamine in huntingtin drives the rate of pathogenesis leading to HD onset, our data from HD subjects do not support this conclusion. Disease-associated HTT alleles with the same pure CAG repeat size may produce different-sized polyglutamine tracts due to variable glutamine-encoding CAA codons, with no commensurate hastening in HD onset due to extra glutamines. Rather, age-at-onset is best explained by a property of the pure CAG repeat separate from its coding potential. We have discovered that HD age-at-onset is modified by genetic variation at 6 loci that encode genes involved in a variety of DNA maintenance processes. These genetic modifiers, in both humans and mouse models, implicate somatic expansion of the CAG repeat rather than encoded polyglutamine as the factor determining age-at-onset. By contrast, symptomatic progression shows at best a weak correlation with CAG repeat size, while duration of manifest disease (i.e., the time from motor diagnosis to death) is independent of CAG repeat length, suggesting that other factors are paramount in determining pathogenesis from onset to death. Overall our findings point to HD as comprising two distinct components: 1) length-dependent somatic expansion of the CAG repeat up to and above a threshold length (rate driver) that then engages toxicity and 2) as yet uncertain mechanism(s) by which the somatically expanded repeat triggers damage when the threshold length is reached (toxicity driver). The nature of the toxicity driver(s) is not yet unequivocal. An effect on huntingtin by above-threshold polyglutamine (rather than continuous length-dependent toxicity) is both attractive and consistent with the effects of long CAG repeats in model systems, but other mechanisms that act at the transcriptional or RNA level have also been suggested as causative. The success of our human genetic strategy has begun to provide new targets for therapeutic interventions to delay or prevent HD onset. In this renewal, we will identify additional rate modifiers to more fully delineate the process of somatic CAG expansion in humans and will extend our strategy to discover modifiers of manifest disease that implicate the nature of the toxicity driver or its damaging consequences. The identification of novel targets, implicated by the natural variation in biological processes ongoing in HD subjects themselves, will provide a firm foundation for developing pharmaceutical interventions that push those processes even farther, toward a strong therapeutic benefit. Thus, the promise of this grant is a new and powerful route to fulfilling the greatest need of both premanifest and manifest HD subjects and their families: effective treatments to block or delay onset and progression of the disease.