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

• 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
• 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

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.

项目摘要 昼夜节律的破坏已被强烈暗示是帕金森氏病的前运动特征 （PD）并已在帕金森氏症动物模型中得到了复制。尚未确定的是 昼夜节律破坏与PD病理生理的一个或多个特征之间的关联。我们在这里 建议使用两种公认的老鼠模型，一种，昼夜节律，“班次”范式和 其他，在黑质纹状体系统中磷酸化α-核蛋白的积累/聚集，α- 综合蛋白（α-Syn）“预成型原纤维（PFF）注射”范式，首次研究昼夜节律 破坏充当突触核酸的加速器及其相关的帕金森氏变性。这 探索性研究将遵循直接的设计。我们将比较之间的突触性程度 有或没有昼夜节律的大鼠以前建立了或 在6个月内，肌醇病和明显的神经变性。根据我们以前研究的数据，我们 将比较突触核酸的程度，包括α-Syn磷酸化和聚集的进展， 多巴胺（DA）表型的丧失（即：酪氨酸羟化酶（Th）的损失和明显的底斑nigra损失 （SN）在存在或不存在昼夜节律的情况下，大鼠之间的神经元。大鼠将在2时牺牲 PFF注射后几个月零6个月，我们以前的工作表明峰α-Syn 聚集发生在2个MO中，并在其他病理之前先于其他病理，包括失去表型，这是首先 在2个MOS上观察到，并且随着时间的推移会进展，并丢失了神经元，纹状体DA及其转运蛋白，以及 PFF注射后6 MOS最明显的细胞因子升高。作为替代衡量 昼夜节律的破坏和对潜在机制的洞察力，我们将测量串行的昼夜节奏 昼夜节律破坏和结束时，基线的皮质酮在基线处 （2和6 mos post-pff）。作为昼夜节律破坏的另一种量度，我们将评估 使用原位杂交终止时核上核的时钟基因PER2。这些目标 探索性原则研究是为了支持或驳斥昼夜节律的相互作用 与PD相关的突触核苷的严重程度，昼夜节律归一化的潜力作为改善 治疗方法以及慢性应激作为促成机制的可能贡献。