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DOI: 10.1055/s-0032-1316308
Pathogenese der Spinalen Muskelatrophie
Pathogenesis of Spinal Muscular AtrophyPublikationsverlauf
Publikationsdatum:
20. Juli 2012 (online)
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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.
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