Molecular Crosstalk Between Circadian Rhythmicity and the Development of Neurodegenerative Disorders
Molecular Crosstalk Between Circadian Rhythmicity and the Development of Neurodegenerative Disorders
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DOI：
10.3389/fnins.2020.00844
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发表时间：
2020-08
影响因子：
4.3
通讯作者：
Arastu Sharma;Sehyun Lee;Hoon-Gu Kim;H. Yoon;Shinwon Ha;Sung-Ung Kang
中科院分区：
文献类型：
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作者：
Arastu Sharma;Sehyun Lee;Hoon-Gu Kim;H. Yoon;Shinwon Ha;Sung-Ung Kang
神经退行性疾病已被证明与昼夜节律具有显着的相互关联性。阿尔茨海默病患者的视交叉上核（SCN）（中枢内源性昼夜节律计时器）表现出高度退化，而帕金森病患者的外周生物钟基因表达则受到高度破坏。神经退行性疾病患者的睡眠模式被破坏非常明显。研究表明，碎片化睡眠会影响阿尔茨海默病患者 tau 蛋白的积累，并且在大量帕金森病患者中观察到快速眼动 (REM) 行为障碍。尽管有大量研究独立分析神经退行性变和昼夜节律功能的机制，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，在这篇综述中，我们探讨了昼夜节律和神经退行性变之间可能的交叉分子机制，特别关注帕金森病。我们提供了 E3 连接酶和聚腺苷二磷酸 (ADP-核糖) 聚合酶 1 (PARP1) 活性对神经退行性病理学潜在影响的证据。除了异常的昼夜节律之外，这些多分子系统的过度活跃所施加的细胞应激和随后的 DNA 损伤信号传导导致广泛的蛋白质聚集，例如 α-突触核蛋白预形成原纤维 (α-Syn PFF)，这表明存在将昼夜节律、PARP1/E3 连接酶活性和帕金森病联系起来的特定分子途径。
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.