RNA-ALS

Amyotrophic lateral sclerosis (ALS) is a devastating, neurodegenerative disorder characterized by muscle weakness progressing to paralysis as a consequence of dysfunction and death of motor neurons. A striking number of genes implicated in pathogenesis encode proteins with functions in RNA metabolism. To address the mechanisms involved and identify common therapeutic targets, we have formed a unique transnational consortium of investigators with expertise in clinical neurology and pathology, RNA metabolism, motor neuron cell biology and experimental modeling. The specific aims build on strong preliminary evidence that miRNAs, regulators of protein-encoding RNAs, are aberrantly expressed in motor neurons in ALS and that neurofilaments are a disease-relevant target. We will characterise and determine the relative role of the miRNAs regulating stability of mRNAs encoding the neurofilament-forming proteins. How their expression is affected in ALS will be defined using autopsy tissue from sporadic and familial ALS patients relative to controls. The function of ALS-relevant miRNAs and consequences of their disruption will be investigated by manipulating their expression in spinal motor neurons in culture, in adult mice and in zebrafish models, and by assessing the impact on multiple functional measures. Finally, we will determine if manipulating key miRNAs is neuroprotective in primary motor neuron culture and zebrafish models of familial ALS. These experiments will establish models and relevant endpoints for future studies to identify novel therapeutics for ALS.