Mart Saarma lab

Contact information

Mart Saarma
Professor
Tel. +358 50 5002726
Fax. +358 2941 59366
e-mail: mart.saarma-at-helsinki dot fi

Institute of Biotechnology
P.O.Box. 56, 00014 University of Helsinki
Street address: Viikinkaari 5D, Biocenter 2

 

 

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GDNF family ligands and receptors

The Glial cell line-Derived Neurotrophic Factor (GDNF) was originally found when searching for a neurotrophic factor which would prevent the continued degeneration of midbrain dopaminergic neurons – a hallmark of Parkinson’s disease (1-4). Although GDNF was identified, cloned and characterized based on its ability to promote the survival and dopamine uptake of dissociated rat embryonic midbrain cultures, this protein soon turned out to be very broadly expressed and crucially important for the development of especially the enteric nervous system and kidney. GDNF is by now known as a multifunctional protein with the capacity to induce cellular survival, proliferation, migration as well as differentiation.

The therapeutic potential of GDNF awoke interest to search for homologous proteins. GDNF soon became the founding member of a small subfamily, GDNF family ligands (GFLs). This family consists of four highly homologous proteins: GDNF, neurturin (NRTN), artemin (ARTN) and persephin (PSPN). It was found that all GFLs signal through the same transmembrane receptor tyrosine kinase REarranged during Transfection (RET), but that GFLs can activate RET only in the presence of a co-receptor: GDNF Family Receptor α (GFRα). Specificity arises through the preferential binding of each GFL to one of four GFRα1-4 co-receptors. Upon activation, RET is transphosphorylated and triggers complex intracellular signaling cascades. We investigate the structure of GDNF and its receptor complexes (5-6), search for new receptors for GFLs (7), study the biology of GDNF and its GFRα1 receptor by analysisng the phenotype for respectice knockout mice and study the role of microRNAs in GDNF regulation. We also investigate the biology and therapeutic effects of NRTN and its mutants, investigate the effects of  proGDNF (8) and search for GFL receptors in Drosophila.

More specifically, Jukka Kallijärvi (PhD) is working on Drosophila models and studying the roles of Ret, Gdnf receptor alpha-like and FasII (dNCAM) genes in Drosophila nervous system development.

JO Andressoo (PhD , sub-group leader) and his team study the role of microRNA regulation of GDNF levels on  brain dopamine  system function, urogential tract,- and enteric nervous system  development using in vitro and in vivo systems.

Pia-Runeberg-Roos (PhD, senior scientist) is working on biologically active, new NRTN variants with decreased binding to heparin and improved spreading in the tissue for the treatment of Parkinson’s disease.

  • Airaksinen, M. S. & Saarma, M. (2002) GDNF family neurotrophic factors: receptor mechanisms, biological functions and therapeutic utility. Nature Rev. Neurosci., 3, 383-394.
  • Bespalov M., Saarma M. (2007) GDNF receptor complex is an emerging drug target. Trends in Pharmacological Sciences28 (2), 68-74.
  • Runeberg-Roos, P., Saarma, M. (2007) Neurotrophic factor receptor RET: structure, cell biology and inherited diseases. Annals of Medicine. 39, 572-580.
  • Andressoo, J.-O. and Saarma, M. (2008) Signalling mechanisms underlying development and maintenance of dopamine neurons. Curr Opin Neurobiol., 18, 297–306.
  • Saarma M., (2009). GFL Neurotrophic Factors: Physiology and Pharmacology. Encyclopedia of Neuroscience, Vol 4, pp. 711-720. (L.R. Squire, Editor. Oxford: Academic Press.
  • Leppänen, V.-M., Bespalov, M. M., Runeberg-Roos, P., Puurand, Ü., Merits, A., Saarma, M. and  Goldman, G. (2004) The structure of GFRa1 domain 3 reveals a novel fold and new insights into GDNF binding and RET activation. EMBO J., 23(7):1452-1462.
  • Parkash, V., Leppänen, V-M., Virtanen, H., Jurvansuu, J. M.,  Bespalov, M. M.,  Sidorova, Y. A., Runeberg-Roos, P.,  Saarma, M. and Goldman, A. (2008) The Structure of the glial cell line-derived neurotrophic factor-coreceptor complex. Insights into RET signalling and heparin binding.  J Biol Chem, 283, (50), 35164-35172.
  • Bespalov MM, Sidorova Y A, Tumova S, Ahonen-Bishopp A, Magalhães AC, Kulesskiy E, Paveliev M, Rivera C, Rauvala H, and Saarma M.(2011) Heparan sulfate proteoglycan syndecan-3 is a novel receptor for GDNF, neurturin and artemin. J. Cell Biol., 192(1):153-169.
  • Lonka-Nevalaita L, Lume M, Leppänen S, Jokitalo E, Peränen J and Saarma M. (2010) Characterization of the intracellular localization, processing and secretion of two GDNF splice isoforms. J. Neurosci. , 30(34):11403-11413.