JPND: Altered mRNA translation as a pathogenic mechanism across neurodegenerative diseases

MRNA翻译的改变与神经退行性疾病有关，包括阿尔茨海默氏症、普里昂病、帕金森氏病和夏科-玛丽-图斯病，以及神经发育疾病，如自闭症谱系障碍。目前，这些疾病还没有根治的方法，其潜在的分子机制也不太清楚，这就排除了合理的药物设计。在这项建议中，我们的目标是获得对这些疾病的分子发病机制的新见解，并找出跨疾病翻译缺陷的共同和不同的机制。细胞和分子机制的复杂性要求采用最先进的方法。我们将在我们的研究中使用的一种这样的方法是基于非规范的氨基酸标记，这将使我们能够在体内特定细胞类型的翻译特征，并在相应疾病的小鼠模型中选择性地识别受影响神经细胞群体中全基因组的蛋白质组变化。我们将使用细胞、小鼠和果蝇疾病模型来评估已发现的与mRNA翻译缺陷和疾病表型相关的分子改变的功能相关性。通过结合该联盟合作伙伴的互补技术和主题专业知识，我们有望对这些可怕疾病及其相关翻译缺陷的分子机制获得前所未有的见解，包括对神经退行性疾病的细胞类型特异性和成年后期发病年龄的见解。这可能为合理设计治疗这些不治之症的药物奠定基础。

Alterations in mRNA translation have been implicated in both neurodegenerative disorders, including Alzheimer's, prion, Parkinson's and Charcot-Marie-Tooth diseases, and neurodevelopmental diseases such as autism spectrum disorders. Currently, no curative treatments are available for these diseases, and the underlying molecular mechanisms are poorly understood, thus precluding rational drug design.In this proposal, we aim to gain novel insights into the molecular pathogenesis of these diseases and to identify common and disparate mechanisms underlying the translation defects across diseases. The complexity of cellular and molecular mechanisms demands state-of-the-art methods. One such approach that we will use in our study is based on non-canonical amino acid tagging that will allow us to cell-type-specifically characterize translation in vivo and to identify genome-wide proteomic changes selectively in the affected neuronal populations in mouse models of the respective diseases. The functional relevance of identified molecular alterations for mRNA translation defects and disease phenotypes will be evaluated using cell, mouse and Drosophila models of disease.By combining the complementary technical and thematic expertises of the consortium partners, we expect to gain unprecedented insights into the molecular mechanisms of these dreadful diseases and their associated translation defects, including insights into the cell type specific nature and late adult age of onset of neurodegenerative disorders. This may lay the foundation for rational drug design for these incurable diseases.