Mart Saarma lab

Contact information

Pia Runeberg-Roos
PhD
Tel. +358 9 191 59378
Fax. +358 9 191 59366
e-mail: pia.runeberg-at-helsinki.fi

Institute of Biotechnology
P.O.Box. 56, 00014 University of Helsinki
Street address: Viikinkaari 9, Biocenter 1

Member of Finnish Centre of Excellence in Molecular and Integrative Neuroscience Research

 

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Pia Runeberg-Roos, PhD

Biologically active NRTN variants with decreased binding to heparin and improved spreading in the tissue for the treatment of Parkinson’s disease
The crystal structure of GDNF and artemin has been solved in complex with their respective co-receptors GDNF family receptor α 1 and 3 (GFRα1 and GFRα3). The structure of NRTN and its receptor is still unsolved. We used the structural information of the GDNF-GFRα1 complex for molecular modelling of NRTN and for the design of four new human NRTN variants with decreased affinity to heparin and better therapeutic properties. We showed that the new NRTN variants are biologically active in vitro and in vivo, have a decreased affinity for heparin and spread better than wild type NRTN in the tissue. In addition the new variants are more resistant to proteolytic degradation than the wild type protein. The new NRTN variants were designed and developed as a potential mean to treat Parkinson’s disease but we are also interested in finding other clinical applications for these variants.

The use of neurotrophic factors for treating Parkinson’s disease aims to support the function and survival of dopaminergic neurons. The cell bodies of these neurons are located in the substantia nigra while their axonal synapses are located in the striatum. In clinical trials neurotrophic factors are delivered to the striatum from where they are supposed to be transported intracellularly to the cell bodies in the substantia nigra. A better spreading in the striatum could lead to an increased uptake by the axons of dopaminergic neurons, but on the other hand a lower affinity for heparin could affect the life cycle of NRTN in some unpredicted way. Therefore it is important to characterise how the new NRTN variants are transported within cells, if they are recycled and when they eventually are degraded. We are studying how the decreased affinity of NRTN to heparan sulphates affects its affinity to the receptor complex, its degradation, its cellular internalisation and retrograde transport along the neuronal axons.

The team working on this project:
Mari Heikkinen, Technician
Elisa Piccinini, Graduate student
Pia Runeberg-Roos, PhD, Docent, Senior scientist
Mart Saarma, Professor

Publications by Pia Runeberg-Roos related to this project:

  1. Leppänen, V. M., Bespalov, M. M., Runeberg‑Roos, P., Puurand, Ü., Merits, A., Saarma, M., Goldman, A. (2004) The structure of GFRα1 domain 3 reveals new insights into GDNF binding and RET activation. EMBO J. 23:1452‑1462.
  2. Yang, J., Lindahl, M., Lindholm, P., Virtanen, H., Coffey, E., Runeberg‑Roos, P., Saarma, M. (2004) PSPN/GFR­α4 has a significantly weaker capacity than GDNF/GFRα1 to recruit RET to rafts, but promotes neuronal survival and neurite outgrowth. FEBS Lett. 569:267‑271.
  3. Virtanen, H., Yang, J., Bespalov, M. M., Hiltunen, J. O., Leppänen, V. M., Kalkkinen, N., Goldman,  A., Saarma, M., Runeberg‑Roos, P. (2005) The first cysteine‑rich domain of the receptor GFRα1 stabilizes the binding of GDNF. Biochem. J. 387:817‑824.
  4. Yang, J., Runeberg‑Roos, P., Leppänen, V. M., Saarma, M. (2007) The mouse soluble GFRα4 receptor activates RET independently of its ligand persephin. Oncogene, 26:3892‑3898.
  5. Runeberg-Roos, P., Virtanen, H., Saarma, M. (2007)  RET(MEN 2B) is active in the endoplasmic reticulum before reaching the cell surface. Oncogene. 2007 26:7909-7915.
  6. Runeberg-Roos, P., Saarma, M. (2007) Neurotrophic factor receptor RET: structure, cell biology and inherited diseases. Annals of Medicine. Review. 39:572-580.
  7. Runeberg-Roos, P., Saarma, M. (2007) Neurotrophic factor receptor RET: structure, cell biol­ogy and inherited diseases. Annals of Medicine. Review. 39:572-580.
  8. Parkash, V., Leppänen, V. M., Virtanen, H., Jurvansuu, J. M., Bespalov, M. M., Sidorova. Y. A.. Runeberg-Roos, P., Saarma, M., Goldman, A. (2008) The structure of the glial cell line-derived neurotrophic factor-coreceptor complex: insights into RET signaling and heparin binding. J. Biol. Chem.283:35164-34172.
  9. Piccinini, E., Kalkkinen, N., Saarma, M., Runeberg-Roos, P. (2011) Glial cell line-Derived Neurotrophic Factor: characterization of mammalian posttranslational modifications. Annals of Medicine, In press.
  10. Runeberg-Roos, P., Bespalov, M. M., Penn, R., Saarma, M. (2010) Improved Neurturin Molecules. Patent application filed on 15.11.2010 as United States Application Number or PCT International Application Number 12/946,167.