Dysregulation of Histone Acetylation in Parkinson's Disease

帕金森病中组蛋白乙酰化的失调

基本信息

批准号：
10855703
负责人：
Frank Soldner
金额：
$ 62.42万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-11 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10855703
关键词：
Acetylation Acyltransferase Adaptor Signaling Protein Affect Aging Alzheimer&apos s Disease Autopsy Biological Brain CRISPR screen Cells Chromatin Cognition Compensation Complex Data Data Set Development Disease Disease model Drug Targeting Ectopic Expression Enzymes Epigenetic Process Etiology Foundations Gene Expression Gene Expression Profile Gene Mutation Genes Genetic Genetic Transcription Goals Histone Acetylation Histone Deacetylase Histone Deacetylase Inhibitor Histones Human Impaired cognition Impairment In Vitro Lewy Bodies Link Mediating Modeling Molecular Mutation Nerve Degeneration Neurodegenerative Disorders Neuronal Dysfunction Neurons PCAF gene Parkinson Disease Pathogenesis Pathologic Processes Pathology Patients Phenotype Physiological Pilot Projects Play Pluripotent Stem Cells Proteins Proteomics Research Reverse Transcription Role SAGA System Testing Therapeutic Tissues Toxic effect Translations age related neurodegeneration alpha synuclein biological adaptation to stress brain tissue epigenetic regulation epigenomics experimental study functional genomics gain of function gene network genome-wide genomic platform histone deacetylase 2 human pluripotent stem cell insight interest loss of function neuron loss neuropathology neuroprotection non-genetic novel novel therapeutics programs protein degradation small molecule small molecule inhibitor sporadic Parkinson&apos s Disease stem cell model tool

项目摘要

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.

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)）的神经元细胞丢失的病因仍不清楚。有令人信服的证据表明组蛋白乙酰化的变化与认知和大脑功能有关。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以及组蛋白乙酰化失调的机制的见解。与年龄相关的神经退行性疾病，如 PD 和阿尔茨海默氏病 (AD) 以及相关痴呆 (AD/ADRD) 在功能上相关。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，我们开发了一种 hPSC-。基于发现平台，提供了一个强大的、可筛选的实验系统，具有神经元细胞中疾病相关的表型。使用这个发现平台，我们对 SILAC 蛋白质组学和全基因组进行了交叉分析。 CRISPR 筛选数据并确定了导致 a-Syn 毒性的组蛋白乙酰化修饰因子，与这些体外组织结果一致，考虑到组蛋白乙酰化的关键功能是调节基因表达，我们在患者死后大脑中发现了类似的变化。我们推测，a-Syn 介导的组蛋白乙酰化修饰酶破坏导致转录失调，导致 PD 和相关突触核蛋白病的神经变性。该提案的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，我们将应用我们的新型功能基因组学平台来确定通过乙酰化功能的获得和丧失来调节组蛋白乙酰化的效果。修饰α-Syn介导的神经元功能损伤和神经元细胞死亡中的酶此外，我们将使用分子和表观基因组学方法来识别与染色质调节的基因表达特征相关的方法。鉴于 a-Syn 病理学是 PD、LBD 和 MSA 的一个关键特征，也是 AD/ADRD 的常见共同病理学，我们将扩大我们的分子和表观遗传学分析，以包括广泛的疾病。基于患者的 hiPSC 模型和死后脑组织，以证实异常的组蛋白乙酰化在 PD 和相关病理学的发病机制中发挥着核心作用。所提出的实验有可能为 PD 的表观遗传学提供重要的机制见解。 PD 和相关的突触核蛋白病。鉴于目前正在开发针对组蛋白修饰剂的药物作为治疗方法，人们对了解如何使用调节组蛋白乙酰化来治疗神经退行性疾病、认知能力下降和衰老产生了很大的兴趣。重要的是，我们的研究结果与衰老相结合。衰老和 AD 的现有数据将有助于在神经退行性疾病和衰老的更广泛背景下解释与 PD 相关的表观遗传变化，并为从功能上理解遗传和非遗传因素如何在病因学中相互作用提供分子起点复杂的神经退行性疾病。