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为帕金森病的前运动特征 (PD)并且已经在帕金森症的动物模型中被复制。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。这里我们 我建议使用两种成熟的大鼠模型，一种是昼夜节律紊乱的“轮班工作”模式，另一种是 其他的，在黑质纹状体系统中磷酸化的α-突触核蛋白的积累/聚集，α-突触核蛋白在黑质纹状体系统中磷酸化的α-突触核蛋白的积累/聚集。 突触核蛋白（α-syn）“预形成的纤维（PFF）注射”范式，首次研究是否昼夜节律 破坏作为突触核蛋白病及其相关帕金森变性的加速剂。这 探索性研究将遵循简单的设计。我们将比较 有或没有昼夜节律紊乱的大鼠，在整个发育过程中持续， 突触核蛋白病和明显的神经变性，超过6个月。根据我们以前的研究数据，我们 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）表型的丧失（即：酪氨酸羟化酶（TH）缺失）和黑质明显缺失 (SN)神经元之间的大鼠在存在或不存在昼夜节律中断。将在2时处死大鼠 根据我们先前的工作，PFF注射后6个月和6个月， 聚集发生在2个月，并先于其他病理，包括TH表型的丧失，这是第一个 在2个月时观察到并随时间推移进展，黑质神经元、纹状体DA及其转运蛋白丢失，以及 细胞因子的升高在PFF注射后6个月最明显。作为一种替代措施， 昼夜节律的破坏和洞察一个潜在的机制，我们将测量昼夜节律的血清 基线时、诱导昼夜节律紊乱后和突触核蛋白病结束时的皮质酮 （PFF后2和6个月）。作为昼夜节律紊乱的额外测量，我们将评估 应用原位杂交技术在视交叉上核中检测到时钟基因Per 2。这些目标 探索性的原理证明研究是支持，或反驳，昼夜节律中断与 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PD的可能性 治疗方法，以及慢性压力作为一种促成机制的可能贡献。