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（包括阿尔茨海默病、朊病毒病、帕金森病和沙克-玛丽-图斯病）和神经发育性疾病（如自闭症谱系障碍）都有关系。目前，这些疾病还没有治愈性的治疗方法，其潜在的分子机制也知之甚少，因此妨碍了合理的药物设计。在这项提议中，我们的目标是获得这些疾病的分子发病机制的新见解，并确定跨疾病翻译缺陷的共同和不同机制。细胞和分子机制的复杂性需要最先进的方法。我们将在研究中使用的一种这样的方法是基于非规范氨基酸标记，这将使我们能够在体内特异性表征细胞类型的翻译，并在相应疾病的小鼠模型中选择性地识别受影响的神经元群体的全基因组蛋白质组学变化。将使用细胞、小鼠和果蝇疾病模型评估已鉴定的mRNA翻译缺陷和疾病表型的分子改变的功能相关性。通过结合联盟合作伙伴的互补技术和专题专业知识，我们期望对这些可怕疾病的分子机制及其相关的翻译缺陷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晚期发病的见解。这可能为这些不治之症的合理药物设计奠定基础。

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.