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.

导致帕金森氏病神经元细胞丧失（PD）和相关的突触核心病的病因，包括路易人体内痴呆（LBD）和多系统萎缩（MSA）仍然未知。有令人信服的证据表明，组蛋白乙酰化的变化在认知和脑功能中暗示，并且异常的组蛋白乙酰化与神经退行性疾病和衰老有关。然而，目前尚无关于原因和失调的组蛋白乙酰化在功能上与年龄相关的神经退行性疾病（如PD和Alzheimer病（AD）和相关痴呆症（AD/ADRD）的功能相关的机理见解。为了在功能上研究组蛋白乙酰化在PD和相关突触核苷的发病机理中的作用，我们开发了一个基于HPSC的发现平台，该平台可提供一个可靠且可筛选的实验系统，并在神经元细胞中具有疾病相关的表型。使用此发现平台，我们将SILAC蛋白质组学和全基因组CRISPR筛分数据相交，并确定了组蛋白乙酰化的修饰符，从而有助于A-Syn毒性。与这些体外结果一致，我们发现患者的死后脑组织发生了类似的变化。考虑到组蛋白乙酰化的关键功能是调节基因表达，我们推测了由A-Syn介导的组蛋白乙酰化修饰酶的破坏导致的转录失调，从而有助于PD及其相关的Synores中的神经变性。该提案的主要目标是确定组蛋白乙酰化在PD和相关的分子水平上的功能作用。具体而言，我们将应用新型的功能基因组学平台来确定通过A-Syn介导的神经元功能和神经元细胞死亡的乙酰化修饰酶的功能的增益和功能丧失调节组蛋白乙酰化的效果。此外，我们将使用分子和表观基因组学方法来识别与A-SYN毒性相关的染色质调节基因表达特征。鉴于A-SYN病理是PD，LBD和MSA的关键特征，也是AD/ADRD中的常见共同病理学，我们将扩展分子和表观远期分析，以包括广泛的基于患者的HIPSC模型和后型HIPSC的模型和后脑脑组织，以证实异常的乙酮乙酰乙酰基乙酰基乙酰基在该病理学中具有PD和PD的中心作用。提出的实验具有对PD和相关突触核苷的表观遗传学的基本机械洞察力的潜力。鉴于目前正在开发靶向组蛋白修饰剂的药物作为治疗，因此有很大的兴趣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。重要的是，我们的发现与可用的衰老数据的整合将允许在神经退行性疾病的更广泛背景下解释与PD相关的表观遗传学变化，并提供一个分子起点，以便在功能上了解遗传和非基因因子在复杂神经变性疾病的病因学中如何相互作用。