Elucidating the role of DNA methylation in the pathophysiology of lewy body diseases.

路易体(路易体)病包括帕金森氏病(PD)、帕金森氏痴呆症(PDD)和路易体痴呆(DLB)。所有这些疾病的特征都是一种名为a-突触核蛋白的蛋白质聚集，在大脑中特定的神经元群体中形成路易小体(Lbs)。这些疾病的临床症状也可能重叠，这可能会使诊断变得困难。这些疾病非常复杂，其确切原因在很大程度上仍不清楚，尽管有人认为遗传和环境因素都可以改变一个人的风险。尽管最近有许多研究寻找可能使个人更容易患上这些疾病的新基因，但大多数已确定的基因变化非常常见，对增加一个人患疾病的可能性只有很小的影响。众所周知，基因的表达不仅依赖于一个人特定的DNA代码(他们的基因组)，而且还可以通过一种额外的信息水平来改变，这种信息被称为“表观基因组”。表观遗传过程是添加到DNA上的化学标签，可以打开和关闭基因，并可能受到外部因素的影响，如细胞居住的环境。LB病患者和未受影响的人之间的主要遗传差异一直很难识别，因此科学家推测，表观遗传差异与这些疾病有关，可能是环境风险改变基因表达的主要方式。在阿尔茨海默病(AD)的案例中，我们和其他人最近发表了一些最早的研究，表明表观遗传变化在AD的大脑样本中持续存在。我们假设表观遗传学变化也在LB病中发挥作用，我们建议我们可以识别表观遗传学特征，根据他们的诊断、遗传学、脑病理程度、症状以及在PD的情况下是否存在痴呆症来区分LBS患者。为了解决这一问题，我们有以下研究目标：目标1：在尸检脑组织样本中鉴定不同类型脑白质瘤的表观遗传学特征。这些可以告诉我们这些疾病之间潜在的生物学差异。目标2：识别与神经病理标记物相关的特定表观遗传学特征，而不考虑临床诊断。这些可以让我们了解在不同疾病中特定细胞类型的选择性脆弱性背后的生物学基础。目的3：确定与精神病相关的特定表观遗传学特征，而不考虑潜在的病理或临床诊断。这可以让我们了解导致这些症状的潜在生物学因素。目标4：识别可以区分PDD和PD的特定表观遗传学特征。这些可以教我们关于潜在的神经生物学和与发展中的痴呆相关的风险因素。为了解决我们的假设，我们建议分析不同路易体疾病在两个大脑区域的表观遗传学变化：黑质(SN)，在疾病的中期阶段受到影响，以及前额叶皮质(PFC)，在疾病的后期阶段受到影响。我们将使用最先进的细胞分类方法来确定哪些细胞类型推动了这些变化，然后将重点放在神经元中的那些变化上。然后，我们将确定这些基因中的哪些在含有Lbs的神经元中发生了特定的改变。最后，我们将通过在细胞培养中使用尖端的基因编辑技术来证明这些基因的表观遗传变化是导致疾病病理的原因。展望未来，由于表观遗传变化可能是可逆的，这些变化可能代表着新的药物靶点。

The Lewy body (LB) diseases include Parkinson's disease (PD), PD dementia (PDD) and Dementia with Lewy bodies (DLB). The hallmarks of all of these diseases are aggregates of a protein called a-synuclein, forming Lewy bodies (LBs) in specific populations of neurons in the brain. The diseases can also have an overlap in clinical symptoms, which can make diagnosis difficult. These diseases are very complex, with their exact cause still largely unknown, although it is suggested that both genetic and environmental factors can alter a person's risk. Although a number of studies have recently searched for new genes that may make an individual more susceptible to these diseases, most of the identified genetic changes are very common, and only have a very modest effect on increasing one's likelihood of developing disease. It is known that the expression of genes relies not only on a person's specific DNA code (their genome), but can also be altered by an extra level of information called the "epigenome". Epigenetic processes are chemical tags added to the DNA that turn genes on and off and can be influenced by external factors such as the environment in which cells dwell. Major genetic differences between the sufferers of people with LB diseases and unaffected individuals have been hard to identify, therefore scientists have speculated that epigenetic differences are involved in the diseases and could be the major way in which environmental risks can alter the expression of genes. In the case of Alzheimer's disease (AD) we, and others, have recently published some of the first studies showing that epigenetic changes are consistently seen in AD brain samples. We hypothesise that epigenetic changes also play a role in LB diseases and we propose that we can identify epigenetic signatures that can distinguish individuals with LBs based on their diagnosis, genetics, degree of brain pathology, symptoms and, in the case of PD, the presence of dementia. In order to address this we have the following research objectives:AIM 1: To identify specific epigenetic signatures of different LB diseases in post-mortem brain samples. These can teach us about the underlying biological differences between these diseases.AIM 2: To identify specific epigenetic signatures that are associated with neuropathological markers, regardless of clinical diagnosis. These can teach us about the biological basis behind the selective vulnerability of particular cell types in the different diseases. AIM 3: To identify specific epigenetic signatures associated with psychosis, regardless of underlying pathology or clinical diagnosis. This can teach us about the underlying biology driving these symptoms.AIM 4: To identify specific epigenetic signatures that can distinguish PDD from PD. These can teach us about the underlying neurobiology and risk factors associated with developing dementia.In order to address our hypotheses we propose to analyse epigenetic changes in the different Lewy body diseases, in two brain regions: the substantia nigra (SN), which is affected in the middle stages of disease, and the prefrontal cortex (PFC), which is affected in the later stages of disease. We will use state-of-the-art cell sorting methods to determine which cell types are driving these changes, before focussing on those altered in neurons. We will then determine which of these genes are specifically altered in neurons containing LBs. Finally, we will demonstrate that epigenetic changes in these genes are causing disease pathology by using cutting-edge genetic editing technology in cell culture. Looking to the future, as epigenetic changes are potentially reversible, these changes could represent novel drug targets.