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.

项目总结 昼夜节律紊乱被认为是帕金森病的运动前期特征 (PD)，并已在帕金森综合症的动物模型中复制。尚未确定的是 昼夜节律紊乱与帕金森病的一个或多个病理生理学特征之间的关系。在这里我们 建议使用两个成熟的大鼠模型，一个是昼夜节律紊乱的大鼠模型，一个是“轮班工作”范式，另一个是 其他，磷酸化的α-突触核蛋白在黑质纹状体系统中的聚集，α-突触核蛋白 突触核蛋白(α-SYN)“预先形成的纤维蛋白(PFF)注射”范式，首次研究是否存在昼夜节律 破坏是联核病及其相关的帕金森氏变性的加速器。这 探索性研究将遵循简单的设计。我们将比较联核症的严重程度和 有或没有昼夜节律紊乱的大鼠在此之前建立，并在整个发育过程中持续 并核病，和明显的神经变性，超过6个月。根据我们之前研究的数据，我们 将比较突触核病的程度，包括α-SYN磷酸化和聚集的进展， 多巴胺(DA)表型丢失(即：酪氨酸羟化酶(TH)丢失)和黑质明显丢失 (SN)存在或不存在昼夜节律干扰的大鼠之间的神经元。老鼠将在2岁时被处死 在我们先前工作的基础上，在注射后6个月和6个月，峰值α-SYN 聚集发生在2个月，并先于其他病理，包括第一个表型的丢失。 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及其转运体的丢失。 注射PFF后6个月细胞因子升高最为明显。作为一种替代措施 并洞察昼夜节律的潜在机制，我们将测量血清的昼夜节律 在诱导昼夜节律紊乱和合并核素病结束后的基线皮质酮 (术后2个月和6个月)。作为昼夜节律紊乱的另一种衡量标准，我们将评估 用原位杂交法研究视交叉上核时钟基因PER2的表达这些项目的目标是 探索性原则证明研究是为了支持或驳斥昼夜节律中断与 与帕金森病相关的联核症的严重程度，昼夜正常化作为改善的可能性 治疗方法，以及慢性应激作为促成机制的可能贡献。