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Pe 6





 

Project: Spinal muscel atrophy - a neurodegenerative disease of spinal motoneurons
(MWK-Niedersachsen for Prof. Dr. Peter Claus)

Spinal muscular atrophy (SMA) is a neurodegenerative disease in children accompanied by a massive loss of motoneurons causing death within the first two years of life. Mutations of the survival of motoneuron (SMN) gene are responsible for this defect. SMN is an assembly protein for RNA-protein complexes in the nucleus and in axons of neurons. However, it is still unclear whether motoneuron cell death is due to nuclear or axonal functions of the SMN protein.

Although SMN is expressed ubiquitously, exclusively motoneurons degenerate in SMA. Initially, SMN has been characterized as a splicing assembly protein. Recently, it has been found that SMN is a general assembly protein for RNA-protein complexes critically involved in survival and maintenance of motoneurons with long axons, e.g. by transporting certain mRNA molecules along these structures. Defects in axonal functions seem to play an important role in the pathophysiology of SMA.

The Claus group has previously demonstrated that SMN is directly involved in the regulation of axonal growth. We have established a cell culture model for SMA which allows biochemical as well as morphometrical analyses of affected neurons. The lack of SMN results in significantly shorter neurites compared to normal conditions. This function is independent of SMN´s well-defined role as a splicing complex assembly protein. Mechanistically, we recently defined a new function of the SMN protein in microfilament metabolism in axons.

Goals

To elucidate the molecular pathology of SMA it is required not only to investigate the nuclear functions of SMN with respect to splicing, but also to extend research to axonal functions of SMN. In our group, we analyze the molecular differences between axonal and nuclear SMN complexes with regard to structure of the complex as well as to functional parameters in neurons by: (1) Differential analyses of protein-protein interactions, (2) Identification of the mechanisms responsible for differential axonal or nuclear localization, and (3) influence of SMN on the signalling cascades responsible for axon growth. The Claus group uses a wide spectrum of state-of-the-art molecular, biochemical and cell biology techniques, e.g. modern methodology of protein interaction research, RNAi and live cell imaging.

 

 

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