Pathogenese der Spinalen Muskelatrophie

Zusammenfassung

Die Spinale Muskelatrophie (SMA) ist in ihrer schwersten Ausprägung (Typ 1) eine letal verlaufende neurodegenerative Erkrankung bei Kindern. Sie stellt die häufigste genetisch-verursachte Todesursache bei diesen Patienten dar und tritt mit einer Häufigkeit von 1:5 000 Geburten auf. Eine Therapiemöglichkeit existiert bisher nicht. Die SMA wird durch Mutation bzw. Deletion des survival of motoneuron 1 Gens (Smn1) hervorgerufen und führt zu einer Degeneration der Motoneurone im Rückenmark. Das SMN-Protein hat wahrscheinlich verschiedene Funktionen: Es dient als Plattform zur Bildung von prä-mRNA Splicing-Komplexen – dieser Splicing-Prozess erfolgt im Zellkern. Darüber hinaus spielt SMN auch eine Rolle in Axonen von Nervenzellen. Unsere Arbeitsgruppe konnte in Vorarbeiten zeigen, dass SMN das Wachstum von Neuriten reguliert und eine Dysregulation des Aktin-Cytoskeletts bei der SMA vorliegt. Dabei wurde ein biochemischer Signalweg identifiziert, der für diese Fehlregulation verantwortlich ist. Es handelt sich dabei um den Rho-Kinase (ROCK) Signalweg – einem wichtigen Schalter für verschiedene neuronale Aktin-abhängige Motilitätsprozesse. Das Molekül ROCK ist dabei auch ein geeignetes Zielmolekül für eine pharmakologische Intervention.

Abstract

Spinal muscular atrophy (SMA) in its most severe form (type 1) is a lethal neurodegenerative disease in children. It represents the most frequent genetic cause of death in this patient group and has a prevalence of 1:5 000 live births. Aa yet there are no options for therapy. SMA is caused by a mutation or, respectively, deletion of the survival motoneuron 1 gene (Smn1) and proceeds through degeneration of motor neurons in the spinal cord. The SMN protein presumably has various functions: it serves as a platform for the formation of pre-mRNA splicing complexes – this splicing process takes place in the cell nucleus. Furthermore, SMN also plays a role in the axons of nerve cells. Preliminary work in our group has demonstrated that SMN regulates the growth of neurites and that in SMA there is a dysregulation of the actin cytoskeleton. The biochemical signalling pathway responsible for this dysregulation has been identified. It involves the rho-kinase (ROCK) signalling pathway – an important switch for various neuronal, actin-dependent processes. The ROCK molecule is thus also a suitable target molecule for pharmacological interventions.

Schlüsselwörter

Rho-Kinase - Aktin - Motoneuron - Wachstumsfaktor

Key words

Rho-Kinase - actin - motoneuron - growth factor

• Literatur

• 1 Jablonka S, Rossell W, Schrank B et al. The role of SMN in spinal muscular atrophy. J Neurol 2000; 247 (Suppl. 01) I37-I42
• 2 Jablonka S, Schrank B, Kralewski M et al. Reduced survival motor neuron (Smn) gene dose in mice leads to motor neuron degeneration: an animal model for spinal muscular atrophy type III. Hum Mol Genet 2000; 9 (03) 341-346
• 3 Terns MP, Terns RM. Macromolecular complexes: SMN – the master assembler. Curr Biol 2001; 11 (21) R862-R864
• 4 Meister G, Eggert C, Fischer U. SMN-mediated assembly of RNPs: a complex story. Trends Cell Biol 2002; 12 (10) 472-478
• 5 Bruns AF, Grothe C, Claus P. Fibroblast growth factor 2 (FGF-2) is a novel substrate for arginine methylation by PRMT5. Biol Chem 2009; 390 (01) 59-65
• 6 Bruns AF, van Bergeijk J, Lorbeer C et al. Fibroblast growth factor-2 regulates the stability of nuclear bodies. Proc Natl Acad Sci USA 2009; 106 (31) 12747-12752
• 7 Claus P, Bruns AF, Grothe C. Fibroblast growth factor-2(23) binds directly to the survival of motoneuron protein and is associated with small nuclear RNAs. Biochem J 2004; 384 (Pt 3) 559-565
• 8 Claus P, Doring F, Gringel S et al. Differential intranuclear localization of fibroblast growth factor-2 isoforms and specific interaction with the survival of motoneuron protein. J Biol Chem 2003; 278 (01) 479-485
• 9 Gringel S, van Bergeijk J, Haastert K et al. Nuclear fibroblast growth factor-2 interacts specifically with splicing factor SF3a66. Biol Chem 2004; 385 (12) 1203-1208
• 10 Jablonka S, Wiese S, Sendtner M. Axonal defects in mouse models of motoneuron disease. J Neurobiol 2004; 58 (02) 272-286
• 11 Zhang HL, Pan F, Hong D et al. Active transport of the survival motor neuron protein and the role of exon-7 in cytoplasmic localization. J Neurosci 2003; 23 (16) 6627-6637
• 12 Rossoll W, Jablonka S, Andreassi C et al. Smn, the spinal muscular atrophy-determining gene product, modulates axon growth and localization of beta-actin mRNA in growth cones of motoneurons. J Cell Biol 2003; 163 (04) 801-812
• 13 Jablonka S, Beck M, Lechner BD et al. Defective Ca2+ channel clustering in axon terminals disturbs excitability in motoneurons in spinal muscular atrophy. J Cell Biol 2007; 179 (01) 139-149
• 14 Zhang H, Xing L, Rossoll W et al. Multiprotein complexes of the survival of motor neuron protein SMN with Gemins traffic to neuronal processes and growth cones of motor neurons. J Neurosci 2006; 26 (33) 8622-8632
• 15 Rossoll W, Kroning AK, Ohndorf UM et al. Specific interaction of Smn, the spinal muscular atrophy determining gene product, with hnRNP-R and gry-rbp/hnRNP-Q: a role for Smn in RNA processing in motor axons?. Hum Mol Genet 2002; 11 (01) 93-105
• 16 Sharma A, Lambrechts A, Haole T et al. A role for complexes of survival of motor neurons (SMN) protein with gemins and profilin in neurite-like cytoplasmic extensions of cultured nerve cells. Exp Cell Res 2005; 309 (01) 185-197
• 17 Giesemann T, Rathke-Hartlieb S, Rothkegel M et al. J Biol Chem 1999; 274: 37908-37914
• 18 van Bergeijk J, Haastert K, Grothe C et al. Valproic acid promotes neurite outgrowth in PC12 cells independent from regulation of the survival of motoneuron protein. Chem Biol Drug Des 2006; 67 (03) 244-247
• 19 van Bergeijk J, Rydel-Konecke K, Grothe C et al. The spinal muscular atrophy gene product regulates neurite outgrowth: importance of the C terminus. FASEB J 2007; 21 (07) 1492-1502
• 20 Nölle A, Zeug A, Vanbergeijk J et al. The spinal muscular atrophy disease protein SMN is linked to the Rho-kinase pathway via profilin. Hum Mol Genet 2011; 20 (24) 4865-4878