title: The spinal muscular atrophy disease protein SMN is linked to the Rho-kinase pathway via profilin.
abstract: Spinal muscular atrophy (SMA), a frequent neurodegenerative disease, is caused by reduced levels of functional survival of motoneuron (SMN) protein. SMN is involved in multiple pathways, including RNA metabolism and splicing as well as motoneuron development and function. Here we provide evidence for a major contribution of the Rho-kinase (ROCK) pathway in SMA pathogenesis. Using an in vivo protein interaction system based on SUMOylation of proteins, we found that SMN is directly interacting with profilin2a. Profilin2a binds to a stretch of proline residues in SMN, which is heavily impaired by a novel SMN2 missense mutation (S230L) derived from a SMA patient. In different SMA models, we identified differential phosphorylation of the ROCK-downstream targets cofilin, myosin-light chain phosphatase and profilin2a. We suggest that hyper-phosphorylation of profilin2a is the molecular link between SMN and the ROCK pathway repressing neurite outgrowth in neuronal cells. Finally, we found a neuron-specific increase in the F-/G-actin ratio that further support the role of actin dynamics in SMA pathogenesis.
authors.affiliation: Institute for Neuroanatomy, Hannover Medical School, Hannover 30623, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Nölle
authors.forename: Andre
authors.initials: A
authors.lastname: Zeug
authors.forename: Jeroen
authors.initials: J
authors.lastname: van Bergeijk
authors.forename: Lars
authors.initials: L
authors.lastname: Tönges
authors.forename: Ralf
authors.initials: R
authors.lastname: Gerhard
authors.forename: Hella
authors.initials: H
authors.lastname: Brinkmann
authors.forename: Sarah
authors.initials: S
authors.lastname: Al Rayes
authors.forename: Niko
authors.initials: N
authors.lastname: Hensel
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Schill
authors.forename: David
authors.initials: D
authors.lastname: Apkhazava
authors.forename: Sibylle
authors.initials: S
authors.lastname: Jablonka
authors.forename: Jana
authors.initials: J
authors.lastname: O'mer
authors.forename: Ratnesh Kumar
authors.initials: RK
authors.lastname: Srivastav
authors.forename: Anne
authors.initials: A
authors.lastname: Baasner
authors.forename: Paul
authors.initials: P
authors.lastname: Lingor
authors.forename: Brunhilde
authors.initials: B
authors.lastname: Wirth
authors.forename: Evgeni
authors.initials: E
authors.lastname: Ponimaskin
authors.forename: Rainer
authors.initials: R
authors.lastname: Niedenthal
authors.forename: Claudia
authors.initials: C
authors.lastname: Grothe
authors.forename: Peter
authors.initials: P
authors.lastname: Claus
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism; D000199:Actins / Q000378:metabolism; D000818:Animals; D004195:Disease Models, Animal; D055785:Gene Knockdown Techniques; D020439:Growth Cones / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051379:Mice; D008954:Models, Biological; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology; D009134:Muscular Atrophy, Spinal / Q000378:metabolism* / Q000473:pathology; D050505:Mutant Proteins / Q000378:metabolism; D020125:Mutation, Missense / Q000235:genetics; D016501:Neurites / Q000378:metabolism; D010766:Phosphorylation; D051304:Profilins / Q000378:metabolism*; D011485:Protein Binding; D051381:Rats; D015398:Signal Transduction; D055533:Survival of Motor Neuron 1 Protein / Q000235:genetics / Q000378:metabolism*; D054460:rho-Associated Kinases / Q000378:metabolism*
chemical_list: D000199:Actins; D050505:Mutant Proteins; D051304:Profilins; D055533:Survival of Motor Neuron 1 Protein; D054460:rho-Associated Kinases