Noelle, Anna, Zeug, Andre ORCID: 0000-0001-9858-5841, van Bergeijk, Jeroen, Toenges, Lars, Gerhard, Ralf, Brinkmann, Hella, Al Rayes, Sarah, Hensel, Niko, Schill, Yvonne, Apkhazava, David, Jablonka, Sibylle ORCID: 0000-0002-4517-3760, O'mer, Jana, Srivastav, Ratnesh Kumar, Baasner, Anne, Lingor, Paul ORCID: 0000-0001-9362-7096, Wirth, Brunhilde ORCID: 0000-0003-4051-5191, Ponimaskin, Evgeni, Niedenthal, Rainer, Grothe, Claudia and Claus, Peter ORCID: 0000-0003-3824-9445 (2011). The spinal muscular atrophy disease protein SMN is linked to the rho-kinase pathway via profilin. Hum. Mol. Genet., 20 (24). S. 4865 - 4879. OXFORD: OXFORD UNIV PRESS. ISSN 1460-2083

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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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Noelle, AnnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zeug, AndreUNSPECIFIEDorcid.org/0000-0001-9858-5841UNSPECIFIED
van Bergeijk, JeroenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Toenges, LarsUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gerhard, RalfUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brinkmann, HellaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Al Rayes, SarahUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hensel, NikoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schill, YvonneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Apkhazava, DavidUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jablonka, SibylleUNSPECIFIEDorcid.org/0000-0002-4517-3760UNSPECIFIED
O'mer, JanaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Srivastav, Ratnesh KumarUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Baasner, AnneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lingor, PaulUNSPECIFIEDorcid.org/0000-0001-9362-7096UNSPECIFIED
Wirth, BrunhildeUNSPECIFIEDorcid.org/0000-0003-4051-5191UNSPECIFIED
Ponimaskin, EvgeniUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Niedenthal, RainerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Grothe, ClaudiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Claus, PeterUNSPECIFIEDorcid.org/0000-0003-3824-9445UNSPECIFIED
URN: urn:nbn:de:hbz:38-483489
DOI: 10.1093/hmg/ddr425
Journal or Publication Title: Hum. Mol. Genet.
Volume: 20
Number: 24
Page Range: S. 4865 - 4879
Date: 2011
Publisher: OXFORD UNIV PRESS
Place of Publication: OXFORD
ISSN: 1460-2083
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
DETERMINING GENE-PRODUCT; MYOSIN LIGHT-CHAIN; NEURITE OUTGROWTH; LIM-KINASE; NEUROMUSCULAR-JUNCTIONS; GROWTH CONES; MOUSE MODELS; SURVIVAL; PHOSPHORYLATION; ACTINMultiple languages
Biochemistry & Molecular Biology; Genetics & HeredityMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/48348

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