Molecular Linkage of Circadian Clocks and Neurodegeneration 

晝夜生理時鐘和神經退化性疾病之分子機制的連結

Student thesis: Doctoral Thesis

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Award date9 Oct 2020

Abstract

Circadian clocks exist in most (if not all) cells and they control a 24-hour cycle of physiological and biological processes throughout the body. The core clock mechanism consists of a transcriptional negative feedback loop, in which the transcription factor BMAL1-CLOCK drives the expression of their target genes including their own inhibitors, Period (Per) and Cryptochrome (Cry), as well as other circadian output genes. As emerging lines of evidence have indicated a reciprocal linkage between altered circadian rhythms and neurodegeneration, it is important to explore the underlying molecular mechanisms involved in this association.

As local clocks are known to control the physiology of local tissues such as the liver and retina, this suggests that local clocks in neurons might have impact on neuronal physiology. To investigate how circadian clocks might control the normal physiology of neurons, we performed RNA-sequencing analysis in Bmal1 deficient neurons (Nestin-cre;Bmal1f/f) and found that Bmal1 deletion induced altered postsynaptic density and compromised neuroprotection.

Given that characterizing the pathogenesis of neurodegeneration is pivotal for further understanding their possible interplay with circadian clocks, we explored global transcriptomic neuronal responses in the toxic models of neurodegeneration, including β-amyloid (Aβ) toxicity and glutamate excitotoxicity using RNA-sequencing. We demonstrated that altered biological functions included synaptic dysfunctions and circadian alterations in Aβ toxicity and glutamate excitotoxicity, and steroid and lipid synthesis was enriched distinctly in glutamate excitotoxicity.

Based on our global transcriptomic results in the Bmal1 deficient neurons and the neuronal responses to Aβ toxicity and glutamate excitotoxicity, we discovered the molecular interplay between circadian clocks and neurodegeneration. First, the expression of PSD 95 was reduced in Bmal1 deficient mouse brains, indicating that altered circadian clocks lead to compromised synaptic function. Second, the core clock mechanism was altered by Aβ toxicity and glutamate excitotoxicity via the downregulation of BMAL1. Third, differentially expressed genes (DEGs) in neurosteroid synthesis due to glutamate excitotoxicity were also downregulated in Bmal1 deficient neurons, showing the impact of circadian clocks on the synthesis of neurosteroids. These results indicate that circadian clocks are intertwined with multiple cellular processes in neurodegeneration and imply circadian clocks as a therapeutic means to intervene the cellular dysregulation that occurs in neurodegenerative diseases.

Overall, through an unbiased transcriptomic approach, our study reveals the molecular interplay between circadian clocks and neurodegeneration and provides a promising direction for further investigations of circadian clocks as a therapeutic means for treating neurodegenerative diseases.