Journal Article

The spinal muscular atrophy disease protein SMN is linked to the rho-kinase pathway via profilin

Anna Nölle, Andre Zeug, Jeroen van Bergeijk, Lars Tönges, Ralf Gerhard, Hella Brinkmann, Sarah Al Rayes, Niko Hensel, Yvonne Schill, David Apkhazava, Sibylle Jablonka, Jana O'mer, Ratnesh Kumar Srivastav, Anne Baasner, Paul Lingor, Brunhilde Wirth, Evgeni Ponimaskin, Rainer Niedenthal, Claudia Grothe and Peter Claus

in Human Molecular Genetics

Volume 20, issue 24, pages 4865-4878
Published in print December 2011 | ISSN: 0964-6906
Published online September 2011 | e-ISSN: 1460-2083 | DOI:
The spinal muscular atrophy disease protein SMN is linked to the rho-kinase pathway via profilin

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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.

Journal Article.  8475 words.  Illustrated.

Subjects: Genetics and Genomics

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