Saturday, April 20, 2024
4/20/2024
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 (a-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 a-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 a-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.
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