帕金森氏症是一種漸進性退化神經系統疾病，會影響人類運動能力，其臨床特徵包括運動和非運動症狀，例如運動遲緩、僵硬、認知或神經行為異常。在帕金森氏症中觀察到的病理特徵包括神經元死亡、神經元外神經黑色素和黑質反應性神經膠質增生。 帕金森氏症主要是由黑質中多巴胺神經元的死亡引起的，但導致多巴胺神經元死亡的確切機制仍不清楚。活性氧類的產生是帕金森氏症的致病因素之一，其因由線粒體功能障礙和多巴胺代謝產生。線粒體功能障礙的原因之一是DNA損傷。DNA中的氧化損傷主要可以通過鹼基切除修復途徑修復，一些證據表明鹼基切除修復途徑可以防止各種環境中的神經毒性。 DNA糖基化酶NTHL1，在線粒體和細胞核中啟動鹼基切除修復途徑的定位和功能。核因子紅細胞2相關因子2 (NRF2)是最重要的氧化反應調節因子之一。越來越多的證據表明NRF2與神經退化性疾病之間存在聯繫。 NRF進入細胞核並與抗氧化反應元件 (ARE) 結合，然後調節細胞保護基因。因此，我們使用單甲基富馬酸 (MMF)增加NRF2調節的抗氧化基因的表達來治療MPTP誘發的PD模型。綜合上面所述，我們發現 NTHL1-/-的小鼠對MPTP的敏感性高於WT小鼠。此外，MMF治療降低了 MPTP 在 NTHL1-/- PD 模型中的毒性。

Parkinson's disease (PD) is a progressive nervous system disorder that affects human motor abilities. The clinical features of PD include motor and non-motor symptoms, such as bradykinesia, rigidity, cognitive or neurobehavioral abnormalities. And the pathological characteristics observed in PD contain neuronal loss, extraneuronal neuromelanin pigment, and reactive gliosis in the substantia nigra (SN). PD is induced mainly by the loss of dopaminergic (DAnergic) neurons in the substantia nigra, yet the exact mechanism that leads to the loss of dopaminergic neurons is still unclear. Reactive oxygen species (ROS) production is one of the causative factors in PD. ROS can be generated by mitochondrial dysfunction and dopamine metabolism. One of the reasons for mitochondrial dysfunction is DNA damage. Oxidative damage in DNA can be repaired primarily via the Base Excision Repair (BER) pathway, and some evidence has shown that BER prevents neurotoxicity in a variety of milieus. The DNA glycosylases, including nth like DNA glycosylase 1 (NTHL1), initiate BER localization and function in mitochondria and the nucleus. Nuclear factor erythroid 2-related factor 2 (Nrf2) is one of the most important oxidative stress regulators. And there is increasing evidence showing the connection between Nrf2 and neurodegenerative disease. Nrf2 enters nuclear and binds to antioxidant response element (ARE), then regulates cytoprotective genes. Therefore, MPTP-injected mice were cotreated with monomethyl fumarate (MMF) to increase Nrf2 and its downstream gene expression. To sum up the above results, we found that NTHL1-/- mice showed higher sensitivity to MPTP than WT mice. Besides, MMF treatment reduces the toxicity of MPTP in NTHL1-/- PD model.

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