Abstract
Parkinson’s disease (PD) is a chronic, progressive neurodegenerative disease, where dopaminergic cells die most prominently in the area of substantia nigra. Neurotrophic factors (NTFs) are secreted proteins, which upon binding to their target receptors trigger survival pathways to prevent neuronal loss. Recently discovered NTFs mesencephalic astrocyte-derived neurotrophic factor (MANF) and conserved dopamine neurotrophic factor (CDNF) most efficiently protect and repair the dopaminergic neurons in the animal 6-OHDA models of PD. However, the neuroprotective mechanism of MANF/CDNF is currently elusive. To this end, we have employed high-resolution NMR spectroscopy to determine three-dimensional structure of full-length human MANF in solution and characterized C-terminal domain as structural unit of MANF protein.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Apostolou A, Shen Y, Liang Y, Luo J, Fang S (2008) Armet, a UPR-upregulated protein, inhibits cell proliferation and ER stress-induced cell death. Exp Cell Res 314:2454–2467
Butte MJ (2001) Neurotrophic factor structures reveal clues to evolution, binding, specificity, and receptor activation. Cell Mol Life Sci 58:1003–1013
Lindholm P, Voutilainen MH, Laurén J, Peränen J, Leppänen VM, Anderssoo JO, Lindahl M, Janhunen S, Kalkkinen N, Timmusk T, Tuominen RK, Saarma M (2007) Novel neurotrophic factor CDNF protects and rescues midbrain dopamine neurons in vivo. Nature 448:73–77
Lindholm P, Peränen J, Anderssoo JO, Kalkkinen N, Kokaia Z, Lindvall O, Timmusk T, Saarma M (2008) MANF is widely expressed in mammalian tissues and differently regulated after ischemic and epileptic insults in rodent brain. Mol Cell Neurosci 39:356–371
Mizobuchi N, Hoseki J, Kubota H, Toyokuni S, Nozaki J, Naitoh M, Koizumi A, Nagata K (2007) ARMET is a soluble ER protein induced by the unfolded protein response via ERSE-II Element. Cell Struct Funct 32:41–50
Parkash V, Lindholm P, Peränen J, Kalkkinen N, Oksanen E, Saarma M, Leppänen VM, Goldman A (2009) The structure of the conserved neurotrophic factors MANF and CDNF explains why they are bifunctional. Protein Eng Des Sel 22:233–241
Permi P, Tossavainen H, Hellman M (2004) Efficient assignment of methyl resonances: enhanced sensitivity by gradient selection in a DE-MQ-(H)CCmHm-TOCSY experiment. J Biomol NMR 30:275–282
Petrova PS, Raibekas A, Pevsner J, Vigo N, Anafi M, Moore MK, Peaire AE, Shridhar V, Smith DI, Kelly J, Durocher Y, Commissiong JW (2003) MANF: a new mesencephalic, astrocyte-derived neurotrophic factor with selectivity for dopaminergic neurons. J Mol Neurosci 20:173–187
Sattler M, Schleucher J, Griesinger C (1999) Heteronuclear multidimensional NMR experiments for the structure determination of proteins in solution employing pulsed field gradients. Prog Nucl Magn Reson Spectr 34:93–158
Wang AC, Grzesiek S, Tschudin R, Lodi PJ, Bax A (1995) Sequential backbone assignment of isotopically enriched proteins in D2O by deuterium-decoupled HA(CA)N and HA(CACO)N. J Biomol NMR 5:376–382
Wishart DS, Sykes BD (1994) The 13-C chemical shift index: a simple method for the identification of protein secondary structure using 13-C chemical shift data. J Biomol NMR 4:171–180
Acknowledgements
We thank Elina Ahovuo and Anne Hakonen for excellent technical assistance. The project was supported by the Academy of Finland grants 122170 and 131144 to P.P.
Author information
Authors and Affiliations
Corresponding authors
Rights and permissions
About this article
Cite this article
Hellman, M., Peränen, J., Saarma, M. et al. 1H, 13C and 15N resonance assignments of the human mesencephalic astrocyte-derived neurotrophic factor. Biomol NMR Assign 4, 215–217 (2010). https://doi.org/10.1007/s12104-010-9251-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12104-010-9251-8