Medizinische Hochschule Hannover : Research interests Prof. Dr. rer. nat. C. Claus

[Translate to Englisch:] Copyright Prof. C. Claus, Neuroanatomie und Zellbiologie, MHH

Project: Spinal muscel atrophy - a neurodegenerative disease of spinal motoneurons

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 1 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 signaling 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.

Selection of recent publications:

Rademacher S., Verheijen B.M., Hensel N., Peters M., Bora G., Brandes G., Vieira de Sá R., Heidrich N., Fischer S., Brinkmann H., van der Pol W.L., Wirth B., Pasterkamp R.J., Claus P. (2017): Metalloprotease-mediated cleavage of PlexinD1 and its sequestration to actin rods in the motoneuron disease Spinal muscular atrophy (SMA). Human Molecular Genetics 26: 3946-3959.

Hensel N., Baskal S., Brinkmann H., Gernert M., Claus P. (2017): ERK and ROCK functionally interact in a signaling network that is compensationally upregulated in Spinal Muscular Atrophy. Neurobiol. Dis. 108: 352-361.

Hensel N. & Claus P. (2018): The actin cytoskeleton in SMA and ALS: How does it contribute to motoneuron degeneration? Neuroscientist 24: 54-72.

Lisa Marie Walter, Marc-Olivier Deguise, Katharina E Meijboom, Corinne A Betts, Nina Ahlskog, Tirsa LE van Westering, Gareth Hazell, Emily McFall, Anna Kordala, Suzan M Hammond, Frank Abendroth, Lyndsay M Murray, Hannah K Shorrock, Domenick A Prosdocimo, Saptarsi M Haldar, Mukesh K Jain, Thomas H Gillingwater, Peter Claus, Rashmi Kothary, Matthew JA Wood, Melissa Bowerman (2018): Interventions targeting glucocorticoid-Krüppel-like factor 15-branched-chain amino acid signaling improve disease phenotypes in spinal muscular atrophy mice. EBioMedicine 31: 226-242.

Lisa M Walter, Christiane E Koch, Corinne A Betts, Nina Ahlskog, Katharina E Meijboom, Tirsa LE van Westering, Gareth Hazell, Amarjit Bhomra, Peter Claus, Henrik Oster, Matthew JA Wood, Melissa Bowerman (2018): Light modulation improves circadian dysregulation and phenotype in spinal muscular atrophy mice. Human Molecular Genetics 27: 3582-3597.

Marc-Olivier Deguise, Giovanni Baranello, Chiara Mastella, Ariane Beauvais, Jean Michaud, Alessandro Leone, Ramona De Amicis, Alberto Battezzati, Christopher Dunham, Kathryn Selby, Jodi Warman Chardon, Hugh J McMillan, Yu-Ting Huang, Natalie L. Courtney, Alannah J. Mole, Sabrina Kubinski, Peter Claus, Lyndsay M. Murray, Melissa Bowerman, Thomas H. Gillingwater, Simona Bertoli, Simon H. Parson, and Rashmi Kothary, PhD (2019): Abnormal fatty acid metabolism is a core component of spinal muscular atrophy. Annals of Clinical and Translational Neurology, 6:1519-1532.

Niko Hensel*, Verena Raker*, Benjamin Förthmann, Nora-Tula Detering, Sabrina Kubinski, Anna Buch, Georgios Katzilieris-Petras, Julia Spanier, Viktoria Gudi8, Sylvia Wagenknecht, Verena Kopfnagel, Thomas Andreas Werfel, Martin Stangel, Andreas Beineke, Ulrich Kalinke, Søren Riis Paludan, Beate Sodeik, and Peter Claus (2019): HSV-1 triggers paracrine fibroblast growth factor response from cortical brain cells via immediate-early protein ICP0. Journal of Neuroinflammation, in press. *, contributed equally.

Lisa Marie Walter, Peter Franz, Robert Lindner, Georgios Tsiavaliaris, Niko Hensel, Peter Claus (2019): Profilin2a-phosphorylation as a regulatory mechanism for actin dynamics. FASEB Journal, in press.