Gridlock in the Nervous System: Altered RNA Localization and Local Translation in Neurodegeneration
Many neurodegenerative diseases exhibit intracellular “traffic jams,” or disrupted transport of proteins and RNA. However, we know little about how transport machinery chooses its cargoes. Our work seeks to elucidate rules for how cargoes are chosen, for example, which RNAs and proteins are carried by which motor proteins. The composition of intracellular cargoes is often disrupted in a subset of neurodegenerative diseases caused by expansions in repetitive DNA sequences, such as Huntington’s Disease, Myotonic Dystrophy, and Amyotrophic Lateral Sclerosis (ALS). While mouse models have provided insights into disease pathogenesis, repetitive sequences in mice do not expand quickly enough to model human disease over decades. Therefore, we propose to accelerate repeat expansion to better model neurodegenerative processes. In summary, both efforts — elucidation of how cargoes are trafficked, and acceleration of repeat expansion in vivo — will provide important insights into neurodegeneration.
Results & Resources
This group developed approaches to study RNA localization patterns in tissues (including computational analysis tools), improved approaches to determine kinesin cargo specificity, and developed new methods to measure DNA repeat expansion lengths. Studies of RNA localization in myofibers revealed that, reminiscent of neuronal contexts, mRNAs require microtubules to exit the perinuclear space. Single molecule repeat length measurements revealed dramatic somatic instability in myotonic dystrophy frontal cortex and strong correlations with transcriptome defects, with broad implications for multiple repeat expansion diseases.