Circadian disruption as an accelerator of synucleinopathy

昼夜节律紊乱是突触核蛋白病的加速因素

基本信息

批准号：
10572194
负责人：
Timothy J. Collier
金额：
$ 43.04万
依托单位：
MICHIGAN STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-15 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10572194
关键词：
Age Age-Months Animal Model Attention Blood Pressure Body Temperature Cells Chronic Chronic stress Circadian Dysregulation Circadian Rhythms Circadian desynchrony Clinical Corpus striatum structure Corticosterone Data Deltastab Development Diurnal Rhythm Dopamine Event Exhibits Female Functional disorder Genes Goals Heart Rate Hydrocortisone In Situ Hybridization Inbred F344 Rats Incidence Injections Intervention Laboratories Light Link Measures Melatonin Modeling Motor Nerve Degeneration Neurons Newly Diagnosed Parkinson Disease Parkinsonian Disorders Pathogenesis Pathology Patients Pharmacology Pharmacotherapy Phenotype Phosphorylation Prevalence Quality of life REM Sleep Behavior Disorder Randomized Rattus Reporting Reproducibility Review Literature Rodent Role Schedule Serum Severities Sleep Stains Substantia nigra structure System Techniques Testing Therapeutic Time Tyrosine 3-Monooxygenase Wakefulness Work alpha synuclein base behavioral response circadian cytokine design dopaminergic neuron experimental study inflammatory marker insight male middle age motor behavior motor symptom nigrostriatal system non-motor symptom nonhuman primate pre-formed fibril shift work suprachiasmatic nucleus synuclein synucleinopathy

项目摘要

PROJECT SUMMARY Disruption of circadian rhythms has been strongly implicated as a pre-motor feature of Parkinson’s Disease (PD) and has been replicated in animal models of parkinsonism. What has not been established is the association between circadian disruption with one or more features of the pathophysiology of PD. Here we propose to use two well-established rat models, one, of circadian disruption, the “shift work” paradigm, and the other, accumulation/aggregation of phosphorylated alpha-synuclein in the nigrostriatal system, the alpha- synuclein (α-syn) “pre-formed fibril (PFF) injection” paradigm, to study for the first time whether circadian disruption acts as an accelerator of synucleinopathy and its associated parkinsonian degeneration. This exploratory study will follow a straightforward design. We will compare the degree of synucleinopathy between rats with or withOUT circadian disruption established before, and continuing throughout development of synucleinopathy, and overt neurodegeneration, over 6 months. Based on data from our previous studies, we will compare the degree of synucleinopathy including progression of α-syn phosphorylation and aggregation, loss of dopamine (DA) phenotype (i.e.: loss of tyrosine hydroxylase (TH)) and overt loss of substantia nigra (SN) neurons between rats in the presence or absence of circadian disruption. Rats will be sacrificed at 2 months and 6 months post-PFF injection based on our previous work demonstrating that peak α-syn aggregation occurs at 2 mos and precedes other pathology including loss of TH phenotype, which is first observed at 2 mos and progresses over time, and loss of nigral neurons, striatal DA and its transporter, and elevation in cytokines that are most pronounced at 6 mos after PFF injection. As a surrogate measure of circadian disruption and insight into a potential mechanism, we will measure the diurnal rhythm of serum corticosterone at baseline, following induction of circadian disruption and at the conclusion of synucleinopathy (2 and 6 mos post-PFF). As an additional measure of circadian disruption we will assess the expression of the clock gene Per2 in the suprachiasmatic nucleus at termination using in situ hybridization. The goal of these exploratory proof-of-principle studies is to support, or refute, an interaction of circadian disruption with the severity of synucleinopathy relevant to PD, the potential for circadian normalization as an ameliorating therapeutic approach, and the possible contribution of chronic stress as a contributing mechanism.

项目概要昼夜节律的破坏与帕金森病的运动前特征密切相关（PD）并已在帕金森病的动物模型中进行了复制，但尚未确定的是。昼夜节律紊乱与 PD 病理生理学的一个或多个特征之间的关联。建议使用两种成熟的大鼠模型，一种是昼夜节律紊乱模型，即“轮班工作”范式，另一种是昼夜节律紊乱模型。其他，磷酸化α-突触核蛋白在黑质纹状体系统中的积累/聚集，α- 突触核蛋白（α-syn）“预形成原纤维（PFF）注射”范式，首次研究昼夜节律是否破坏是突触核蛋白病及其相关帕金森病变性的加速器。探索性研究将遵循简单的设计，我们将比较两者之间的突触核蛋白病程度。具有或不具有昼夜节律紊乱的大鼠之前已建立并在整个发育过程中持续存在根据我们之前研究的数据，我们在 6 个月内发现了突触核蛋白病和明显的神经变性。将比较突触核蛋白病的程度，包括 α-syn 磷酸化和聚集的进展，多巴胺 (DA) 表型丧失（即：酪氨酸羟化酶 (TH) 丧失）和黑质明显丧失在存在或不存在昼夜节律紊乱的情况下，大鼠之间的(SN)神经元将在2时处死。根据我们之前的工作，PFF 注射后几个月和 6 个月，α-syn 峰值聚集发生在 2 个月时，先于其他病理，包括 TH 表型丧失，这是第一个在 2 个月时观察到并随着时间的推移而进展，黑质神经元、纹状体 DA 及其转运蛋白的损失，以及 PFF 注射后 6 个月时细胞因子的升高最为明显。昼夜节律紊乱和对潜在机制的洞察，我们将测量血清的昼夜节律基线时、昼夜节律紊乱诱导后和突触核蛋白病结束时的皮质酮（PFF 后 2 个月和 6 个月）作为昼夜节律紊乱的额外测量，我们将评估的表达。使用原位杂交终止视交叉上核中的时钟基因 Per2。探索性原理验证研究的目的是支持或反驳昼夜节律紊乱与与 PD 相关的突触核蛋白病的严重程度，昼夜节律正常化作为改善的潜力治疗方法，以及慢性压力作为促进机制的可能贡献。