Repeat-induced mutagenesis in Huntington's disease

亨廷顿病(HD)是一种脑细胞(神经元)丢失的脑部疾病。这种神经元的丧失会导致运动、记忆、思维和行为的问题。随着时间的推移，这些症状逐渐恶化，导致在第一次出现症状后15-20年内死亡。没有可用的治疗方法可以减缓或阻止这种情况的发生。HD是由一种名为Huntingtin的基因中特定DNA序列重复次数的增加引起的。重复的DNA序列基序为CAG。在未受影响的人群中，CAG重复次数很少(少于36次)。在患有HD的人中，有更多的重复(超过39岁)，更长的重复会导致更严重的症状，这些症状在更年轻的时候就会出现。换句话说，当一个人有更多的重复基因时，疾病就会更严重。重要的是，DNA序列中的重复数可以随着时间的推移而增加。这一过程受到靠近CAG重复序列的其他小DNA序列的影响，因此可以在疾病严重程度中发挥作用。我们目前还不知道这些额外序列的变化是如何在人身上产生的。本研究旨在寻找这些问题的答案。为此，我们将使用最先进的技术，使我们能够研究我们感兴趣的DNA序列，从HD患者的细胞中收集，在实验室培养的细胞中，并在试管中使用纯化的蛋白质和DNA。我们将收集人的细胞，看看我们是否能在受HD影响的人身上发现与我们在实验室培养的细胞中发现的相同的结果。我们还将突变细胞中的特定序列，并研究它们如何影响重复区域周围的突变外观。我们将获得的结果将有助于我们更好地理解重复序列是如何产生的，以及它们是否与疾病症状相关。

Huntington's disease (HD) is a brain disorder in which brain cells (neurons) are lost. This loss of neurons causes problems with movement, memory, thinking, and behaviour. These symptoms gradually worsen over time, leading to death 15-20 years after the first symptoms are seen. No treatment is available that can slow or stop this from happening.HD is caused by an increase in the number of repeats of a specific DNA sequence, within a gene called huntingtin. The repeating DNA sequence motif is CAG. In unaffected people, the number of CAG repeats is small (less than 36). In people with HD, there are more repeats (over 39), with longer repeats leading to worse symptoms that appear at a younger age. In other words, the disease is more severe when a person has more repeats. Importantly, the number of repeats in the DNA sequence can increase in size over time. This process is affected by other small DNA sequences close to the CAG repeat sequence and can therefore play a part in disease severity. We do not currently understand how changes in these additional sequences are generated in people. This study aims to find the answer to these questions. To do this, we will use state of the art techniques that allow us to investigate the DNA sequences we are interested in, in cells collected from people affected by HD, in cells grown in the laboratory, and using purified proteins and DNA in a test tube. We will collect cells from people to see if we can find the same results in people affected by HD that we find in cells grown in the laboratory. We will also mutate specific sequences in cells and study how they affect the appearance of mutations around the repeat tract.The results we will obtain will improve our understanding of how sequences near repeats are generated and whether they correlate with disease symptoms.