Neuronal ceroid lipofuscinosis (NCL) is one of the most prevalent neurodegenerative disorders of early life, Parkinson’s disease (PD) is the most common neurodegenerative disorder of midlife, while Alzheimer’s disease (AD) is the most common neurodegenerative disorder of late life. While they are phenotypically distinct, recent studies suggest that they share a biological pathway, retromer-dependent endosomal trafficking. A retromer is a multimodular protein assembly critical for sorting and trafficking cargo out of the endosome. As a lysosomal storage disease, all 13 of NCL’s causative genes affect endolysosomal function, and at least four have been directly linked to retromer. PD has several known causative genes, with one directly linked to retromer and others causing endolysosomal dysfunction. AD has over 25 causative genes/risk factors, with several of them linked to retromer or endosomal trafficking dysfunction. In this article, we summarize the emerging evidence on the association of genes causing NCL with retromer function and endosomal trafficking, review the recent evidence linking NCL genes to AD, and discuss how NCL, AD, and PD converge on a shared molecular pathway. We also discuss this pathway’s role in microglia and neurons, cell populations which are critical to proper brain homeostasis and whose dysfunction plays a key role in neurodegeneration.

中文翻译：

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阿尔茨海默氏病，帕金森氏病和神经元性脂质脂肪增多症的内体贩运。

神经元类脂褐质沉着病（NCL）是生命早期最普遍的神经退行性疾病之一，帕金森氏病（PD）是中年最常见的神经退行性疾病，而阿尔茨海默氏病（AD）是晚年最常见的神经退行性疾病。尽管它们在表型上是不同的，但最近的研究表明它们共享生物学途径，即依赖于前体的内体运输。逆转录酶是一种多模块蛋白装配体，对于将货物分类和运输出内体至关重要。作为溶酶体贮积病，NCL的所有13个致病基因均影响溶酶体功能，并且至少有四个与逆转录酶直接相关。PD有几种已知的致病基因，其中一种直接与逆转录酶相关，另一种引起溶酶体功能障碍。AD有25种以上的致病基因/风险因素，其中一些与逆转录或内体运输功能障碍有关。在本文中，我们总结了导致NCL的基因与逆转录酶功能和内体运输相关的新兴证据，回顾了将NCL基因与AD关联的最新证据，并讨论了NCL，AD和PD如何在共享的分子途径上融合。我们还讨论了该途径在小胶质细胞和神经元中的作用，小胶质细胞和神经元对正常的脑稳态至关重要，并且其功能障碍在神经变性中起关键作用。和PD汇聚在一个共享的分子途径上。我们还讨论了该通路在小胶质细胞和神经元中的作用，这些细胞群对正常的脑稳态至关重要，并且其功能障碍在神经变性中起关键作用。和PD汇聚在一个共享的分子途径上。我们还讨论了该途径在小胶质细胞和神经元中的作用，小胶质细胞和神经元对正常的脑稳态至关重要，并且其功能障碍在神经变性中起关键作用。