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

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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.