Dysregulation of Histone Acetylation in Parkinson's Disease

导致帕金森病（PD）和相关突触核蛋白病（包括路易体痴呆（LBD）和多系统萎缩（MSA））神经元细胞损失的病因尚不清楚。有令人信服的证据表明，组蛋白乙酰化的变化与认知和脑功能有关，异常的组蛋白乙酰化与神经退行性疾病和衰老有关。然而，目前还没有关于其原因的机制见解，以及失调的组蛋白乙酰化如何在功能上与年龄相关的神经退行性疾病(如PD和阿尔茨海默病（AD）和相关痴呆（AD/ADRD）相关。为了从功能上研究组蛋白乙酰化在PD和相关突触核蛋白病发病机制中的作用，我们开发了一个基于hpsc的发现平台，该平台提供了一个强大的、可筛选的实验系统，可以在神经细胞中检测疾病相关表型。利用这一发现平台，我们将SILAC蛋白质组学和全基因组crispr筛选数据相结合，鉴定出组蛋白乙酰化修饰因子对a-Syn毒性的影响。与这些体外实验结果一致，我们在患者死后的脑组织中发现了类似的变化。考虑到组蛋白乙酰化的一个关键功能是调节基因表达，我们推测由a- syn介导的组蛋白乙酰化修饰酶的破坏导致的转录失调，有助于PD的神经变性和相关的突触核蛋白病。本研究的主要目的是在分子和细胞水平上确定组蛋白乙酰化在PD和相关突触核蛋白病中的功能作用。具体来说，我们将应用我们新的功能基因组学平台来确定通过乙酰化修饰酶的功能获得和丧失来调节组蛋白乙酰化在a- syn介导的神经元功能损伤和神经元细胞死亡中的作用。此外，我们将使用分子和表观基因组学方法来鉴定与a-Syn毒性相关的染色质调控基因表达特征。鉴于a- syn病理是PD、LBD和MSA的关键特征，也是AD/ADRD的常见共同病理，我们将扩大我们的分子和表观遗传学分析，包括广泛的患者衍生的基于hipsc的模型和死后脑组织，以证实异常组蛋白乙酰化在PD和相关病理的发病机制中起核心作用。提出的实验有可能为PD和相关突触核蛋白病的表观遗传学提供基本的机制见解。考虑到靶向组蛋白修饰剂的药物目前正被开发为治疗方法，了解如何调节组蛋白乙酰化可用于治疗神经退行性疾病，认知能力下降和衰老是相当有兴趣的。重要的是，将我们的发现与衰老和AD的现有数据相结合，将允许在更广泛的神经退行性疾病和衰老背景下解释pd相关的表观遗传变化，并提供一个分子起点，从功能上理解遗传和非遗传因素如何在复杂神经退行性疾病的病因学中相互作用。

The etiology leading to neuronal cell loss in Parkinson’s disease (PD) and related synucleinopathies including Lewy Body Dementia (LBD) and Multiple system atrophy (MSA) remains unknown. There is compelling evidence that changes in histone acetylation are implicated in cognition and brain function and that aberrant histone acetylation is associated with neurodegenerative diseases and aging. However, there is currently no mechanistic insight about the cause and how dysregulated histone acetylation is functionally linked to age-related neurodegenerative disorders such as PD and Alzheimer's disease (AD) and related dementias (AD/ADRD). To functionally investigate the role of histone acetylation in the pathogenesis of PD and related synucleinopathies, we have developed a hPSC-based discovery platform that provides a robust, and screenable experimental system with disease-relevant phenotypes in neuronal cells. Using this discovery platform, we intersected SILAC proteomics and genome-wide CRISPR-screening data and identified modifiers of histone acetylation to contribute to a-Syn toxicity. Consistent with these in vitro results, we find similar changes in patients’ postmortem brain tissue. Considering that a key function of histone acetylation is to modulate gene expression, we speculate the dysregulated transcription, resulting from a-Syn-mediated disruption of histone acetylation modifying enzymes, contributes to the neurodegeneration in PD and related synucleinopathies. The main goal of this proposal is to determine the functional role of histone acetylation in PD and related synucleinopathies at the molecular and cellular level. Specifically, we will apply our novel functional genomics platform to determine the effect of modulating histone acetylation by gain and loss of function of acetylation modifying enzymes in a-Syn-mediated impairment of neuronal function and neuronal cell death. In addition, we will use molecular and epigenomics approaches to identify the chromatin regulated gene expression signature associated with a-Syn toxicity. Given that a-Syn pathology is a key feature of PD, LBD, and MSA, as well as a common co-pathology in AD/ADRD, we will expand our molecular and epigenetic analysis to include a wide range of patient-derived hiPSC-based models and postmortem brain tissue to confirm that aberrant histone acetylation plays a central role in the pathogenesis of PD and related pathologies. The proposed experiments hold the potential to offer essential mechanistic insights into the epigenetics of PD and related synucleinopathies. Given that drugs targeting histone modifiers are currently being developed as therapeutics, there is considerable interest in understanding how modulating histone acetylation could be used to treat neurodegenerative disease, cognitive decline, and aging. Importantly, the integration of our findings with available data for aging and AD will allow the interpretation of PD-associated epigenetic changes in a broader context of neurodegenerative diseases and aging and provide a molecular starting point to functionally understand how genetic and non-genetic factors interact in the etiology of complex neurodegenerative diseases.