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.

Cerebral cavernous malformations (CCMs) are vascular lesions mostly located in the central nervous system, leading to epileptic seizures and hemorrhagic stroke. The disease occurs as a sporadic and a familial form. The autosomal dominant form of CCM has a prevalence of 1/10.000 and is characterized by the presence of multiple CCM lesions causing recurrent cerebral hemorrhages. Deep seated lesions are not accessible to neurosurgery and novel pharmacological approaches are desperately needed for those severe forms of the disease. Our collaboration supports the hypothesis that unbiased pharmacological suppression screens in the nematode C. elegans (Canadian partners) and in the small vertebrate model organism zebrafish (German partners) will help to identify compounds with a beneficial effect for the treatment or prevention of CCMs. By identifying compounds that suppress ccm mutant phenotypes in both C. elegans and zebrafish, we will gain insight into those molecular pathways and cell biological processes that are relevant for the CCM disease. The French partner has generated inducible murine knockout models that mimic human cerebral and retinal CCM lesions. The efficacy of the most promising compounds will be assessed in these mouse models. Our collaboration brings together the power of genetics of the C. elegans and zebrafish models with the murine disease models that are not suitable for unbiased high-throughput compound screening. The added benefit of our transnational consortium is required for the identification of compounds with a beneficial effect in the CCM disease