自噬、帕金森氏症和多巴胺能神经元

自噬功能障碍与PD患者体内α-突触核蛋白的积累和疾病进展密切相关。Wu等人（Wu，2011）发现，散发性帕金森病患者体内包括LAMP2 和MAP1LC3在内的关键自噬基因的表达发生了显著变化。这些自噬基因的差异表达表明，通过PCR（qPCR）等基因表达谱分析方法以及RNA-Seq等高通量测序技术，这些基因有可能成为帕金森病的临床生物标记。

在帕金森氏症小鼠模型中，早期诱导自噬与雷帕霉素一起使用，显示出神经保护作用（Pupyshev，2019）。同样，在6-羟基多巴胺（6-OHDA）模型中，用3-甲基腺嘌呤抑制自噬，可以防止多巴胺能神经元的细胞死亡。这些对比鲜明的发现凸显了自噬在帕金森氏症中复杂且阶段依赖性的作用。

通过选择性自噬（称为线粒体自噬）降解有缺陷的线粒体是细胞稳态的重要机制。越来越多的研究表明线粒体功能障碍是PD发病的主要原因（Moon，2015）。这些线粒体可能是α-突触核蛋白诱导损伤的目标，因为果蝇模型研究表明，α-突触核蛋白的突变形式可以抑制线粒体自噬。然而，这种抑制作用背后的精确分子机制尚未完全清楚（Krzystek，2021 ；Kinnart，2024）。

溶酶体脂质代谢是指溶酶体降解和回收细胞内脂质以维持体内平衡的过程。在中枢神经系统中，脂质对于神经元生成、神经元之间的突触形成以及轴突绝缘至关重要。在帕金森病中，调节溶酶体代谢的基因突变——GBA 、GALC、SMPD1和ASAH1——会增加患病风险。然而，脂质代谢异常导致帕金森病的潜在机制尚不清楚。

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α-突触核蛋白：一种 突触前神经元蛋白 ，在遗传学和神经病理学上与帕金森病（PD）有关。

自噬：源自 希腊语，意为“自我吞噬”，由比利时生物化学家克里斯蒂安·德·杜夫（Christian de Duve）提出，用于描述细胞内溶酶体降解过程，以清除和回收细胞碎片。

生物标记：生物状态或状况的可测量指标。生物标记常用于医学和研究领域，以检测或监测疾病的存在、进展或严重程度，以及评估治疗效果。

伴侣介导的细胞自噬：一种 选择性细胞自噬，利用蛋白质作为伴侣，将其他异常蛋白质引导至溶酶体进行降解。

多巴胺能神经元 ：产生并释放多巴胺的神经元 ，多巴胺是一种神经递质，参与运动功能、奖励处理、行为和情绪。这些神经元主要产生于大脑中称为黑质的区域。

电子显微镜（EM）：一种 利用电子束以纳米级分辨率观察结构的成像技术 。

外泌体：真核细胞分泌的细胞外膜囊泡，用于在细胞之间运输各种生物分子。

路易体：大量α-突触核蛋白在神经元内堆积。这些团块是帕金森氏病的典型特征。

边缘系统 ：大脑中负责情绪、行为、动机和记忆的复杂结构网络 。

溶酶体 ：真核细胞中的一种 膜结合的降解细胞器 ，负责消化脂质、蛋白质和其他大分子。

Microglia：大脑和脊髓中的一种神经胶质细胞。Microglia细胞约占大脑细胞总数的10-15%，是中枢神经系统的主要免疫细胞。这些细胞对于维持体内平衡、清除细胞碎片以及提供大脑内的关键支持功能至关重要。

神经退化：一个复杂的多因素过程，会导致神经元丢失。

帕金森氏症（PD）：一种神经退行性疾病，其特征是(a) 与运动相关的（运动）症状，包括静止性震颤、运动迟缓、僵硬和姿势不稳，与黑质多巴胺能神经元的丧失有关；以及 (b) 非运动症状，包括焦虑、抑郁、冷漠、幻觉、便秘、体位性低血压、睡眠障碍、嗅觉减退/丧失和认知障碍。

错误折叠的蛋白质：蛋白质 由氨基酸线性链组成，必须折叠成功能性三维结构。当这些链不能正确折叠时，产生的蛋白质就会呈现异常形状。这些蛋白质通常不溶于水，并破坏正常的细胞过程。错误折叠的蛋白质的积累与多种神经退行性疾病密切相关，包括阿尔茨海默氏病（AD）、帕金森氏病（PD）、亨廷顿氏病（HD）和肌萎缩性侧索硬化症（ALS）。

蛋白质聚集 ：细胞内或细胞周围聚集的错折叠蛋白质团块 ，就像一团团纠结的线球 。

黑质 ：位于中脑 的神经核 ，作为基底神经节回路的一部分，在调节运动和奖励功能方面发挥着关键作用。

跨反应性43 kDa DNA结合蛋白（TDP-43）：一种高度保守的核RNA/DNA结合蛋白，由TARDBP基因编码，参与RNA加工的调节。