Neurodegenerative disorders have been shown to exhibit substantial interconnectedness with circadian rhythmicity. Alzheimer’s patients exhibit high degradation of the suprachiasmatic nucleus (SCN), the central endogenous circadian timekeeper, and Parkinson’s patients have highly disrupted peripheral clock gene expression. Disrupted sleep patterns are highly evident in patients with neurodegenerative diseases; fragmented sleep has been shown to affect tau-protein accumulation in Alzheimer’s patients, and rapid eye movement (REM) behavioral disorder is observed in a significant amount of Parkinson’s patients. Although numerous studies exist analyzing the mechanisms of neurodegeneration and circadian rhythm function independently, molecular mechanisms establishing specific links between the two must be explored further. Thus, in this review, we explore the possible intersecting molecular mechanisms between circadian rhythm and neurodegeneration, with a particular focus on Parkinson’s disease. We provide evidence for potential influences of E3 ligase and poly adenosine diphosphate (ADP-ribose) polymerase 1 (PARP1) activity on neurodegenerative pathology. The cellular stress and subsequent DNA damage signaling imposed by hyperactivity of these multiple molecular systems in addition to aberrant circadian rhythmicity lead to extensive protein aggregation such as α-synuclein pre-formed fibrils (α-Syn PFFs), suggesting a specific molecular pathway linking circadian rhythmicity, PARP1/E3 ligase activity, and Parkinson’s disease.

中文翻译：

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昼夜节律与神经退行性疾病发展之间的分子串扰

神经退行性疾病已被证明与昼夜节律有很大的联系。阿尔茨海默氏症患者表现出视交叉上核 (SCN)、中枢内源性昼夜节律计时器的高度退化，而帕金森氏症患者的外周时钟基因表达高度紊乱。神经退行性疾病患者的睡眠模式中断非常明显；碎片化的睡眠已被证明会影响阿尔茨海默病患者的 tau 蛋白积累，并且在大量帕金森病患者中观察到快速眼动 (REM) 行为障碍。尽管存在许多独立分析神经变性和昼夜节律功能的机制的研究，但必须进一步探索在两者之间建立特定联系的分子机制。因此，在本次审查中，我们探索昼夜节律和神经变性之间可能的交叉分子机制，特别关注帕金森病。我们为 E3 连接酶和聚二磷酸腺苷 (ADP-核糖) 聚合酶 1 (PARP1) 活性对神经退行性疾病的潜在影响提供了证据。除了异常的昼夜节律外，这些多分子系统的过度活跃所施加的细胞压力和随后的 DNA 损伤信号导致广泛的蛋白质聚集，例如 α-突触核蛋白预形成的原纤维 (α-Syn PFFs)，表明连接昼夜节律的特定分子途径节律性、PARP1/E3 连接酶活性和帕金森病。我们为 E3 连接酶和聚二磷酸腺苷 (ADP-核糖) 聚合酶 1 (PARP1) 活性对神经退行性疾病的潜在影响提供了证据。除了异常的昼夜节律外，这些多分子系统的过度活跃所施加的细胞压力和随后的 DNA 损伤信号导致广泛的蛋白质聚集，例如 α-突触核蛋白预形成的原纤维 (α-Syn PFFs)，表明连接昼夜节律的特定分子途径节律性、PARP1/E3 连接酶活性和帕金森病。我们为 E3 连接酶和聚二磷酸腺苷 (ADP-核糖) 聚合酶 1 (PARP1) 活性对神经退行性疾病的潜在影响提供了证据。除了异常的昼夜节律外，这些多分子系统的过度活跃所施加的细胞压力和随后的 DNA 损伤信号导致广泛的蛋白质聚集，例如 α-突触核蛋白预形成的原纤维 (α-Syn PFFs)，表明连接昼夜节律的特定分子途径节律性、PARP1/E3 连接酶活性和帕金森病。