fr-180204 and Muscular-Atrophy--Spinal

Rho-kinase (ROCK) as well as extracellular signal regulated kinase (ERK) control actin cytoskeletal organization thereby regulating dynamic changes of cellular morphology. In neurons, motility processes such as axonal guidance and neurite outgrowth demand a fine regulation of upstream pathways. Here we demonstrate a bilateral ROCK-ERK information flow in neurons. This process is shifted towards an unidirectional crosstalk in a model of the neurodegenerative disease Spinal Muscular Atrophy (SMA), ultimately leading to neurite outgrowth dysregulations. As both pathways are of therapeutic relevance for SMA, our results argue for a combinatorial ROCK/ERK-targeting as a future treatment strategy.

Topics: Actin Cytoskeleton; Amides; Animals; Cell Line; Cell Proliferation; Enzyme Inhibitors; Extracellular Signal-Regulated MAP Kinases; Mice; Muscular Atrophy, Spinal; Neurites; PC12 Cells; Pyrazoles; Pyridazines; Pyridines; Pyrimidines; Rats; Receptor Protein-Tyrosine Kinases; Receptors, Fibroblast Growth Factor; rho-Associated Kinases; RNA Interference; RNA, Small Interfering; SMN Complex Proteins