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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Biology of CDNF/MANF protein family

CDNF and MANF form a novel, evolutionary conserved protein family with neurotrophic activities (1). CDNF was originally identified and characterized by our group (2, 3) and is homologous to mammalian MANF protein (4). CDNF-MANF homologue gene is also found in invertebrate animals, such as D. melanogaster and C. elegans, in which no other neurotrophic factors have been identified so far. In cells, CDNF/MANF proteins are located in the ER and are also secreted.

Parkinson’s disease (PD) is a progressive neurodegenerative disorder in which midbrain dopaminergic neurons are affected. In collaboration with Prof. Raimo Tuominen’s and Prof. Barry Hoffer’s groups we have shown that striatal delivery of CDNF protects midbrain dopaminergic neurons and restores their function in a rat 6-OHDA model (2, 5) and in a mouse MPTP model (6) of PD in vivo. Similarly with CDNF, also MANF shows protective effects on dopaminergic neurons in a rat 6-OHDA model of PD (7). In collaboration with Tapio Heino’s group we have shown that Drosophila MANF is needed for the maintenance of dopaminergic neurites and dopamine levels in the fly and is a functional ortholog of human MANF and CDNF (8). Based on our studies CDNF is a promising candidate for the treatment of PD. In collaboration with HermoPharma Ltd our aim is to take CDNF to human clinical trials on PD patients.

The mechanism of action and binding partners of CDNF and MANF are still unknown. We have resolved the crystal and NMR solution structure of human MANF and CDNF (9, 10, Hellman et al. unpublished) and a partial crystal structure of human CDNF (9). The structure of CDNF/MANF proteins consists of two domains, an amino-terminal saposin-like domain and a C-terminal SAP-domain that are connected by a flexible linker. We have recently shown that intracellular MANF, presumably via the SAP-domain, can protect SCG neurons against Bax-mediated apoptotic cell death (10). MANF is located in the ER and is able protect cells against ER stress (11). We are currently studying the cytoprotective and neuroprotective properties of MANF and CDNF by cell and molecular biology methods.

To understand the biological roles for the novel neurotrophic factors CDNF and MANF, we have created both conventional and conditional gene knockout mice. Preliminary results show interesting findings in the nervous system (Lindahl et al., unpublished) but also outside the nervous system (12).

 

1. Lindholm P, Saarma M. (2010) Novel CDNF/MANF family of neurotrophic factors, Dev Neurobiol. 70:360-371.

2. Saarma M, Laurén J, Lindholm P, Timmusk T and Tuominen RK. Neurotrophic factor protein and uses thereof. Patent US 7,452,969.

3. Lindholm, P., Voutilainen, M .H., Laurén, J., Peränen, J., Leppänen, V-M., Andressoo, J-O., Lindahl, M., Janhunen, S.,  Kalkkinen, N., Timmusk, T., Tuominen, RK.. and  Saarma, M. (2007) Novel neurotrophic factor CDNF protects and rescues midbrain dopaminergic neurons in vivo. Nature, 448:73-77.

4. Petrova, P., Raibekas, A., Pevsner, J., Vigo, N., Anafi, M., Moore, M.K., Peaire, A.E., Shridhar, V., Smith, D.I., Kelly, J., Durocher, Y. and Commissiong, J.W. (2003) MANF: a new mesencephalic, astrocyte-derived neurotrophic factor with selectivity for dopaminergic neurons. J Mol Neurosci. 20:173-188.

5. Voutilainen MH, Bäck S, Peränen J, Lindholm P, Raasmaja A, Männistö PT, Saarma M, Tuominen RK. (2011) Chronic infusion of CDNF prevents 6-OHDA-induced deficits in a rat model of Parkinson's disease. Exp Neurol. 228:99-108.

6. Airavaara, M., Harvey, B.K., Voutilainen, M.H., Shen, H., Chou, J., Lindholm, P., Lindahl, M., Tuominen, R.K., Saarma, M., Wang, Y., Hoffer, B. (2011) CDNF protects the nigrostriatal dopamine system and promotes recovery after MPTP treatment in mice. Cell Transplant. in press

7. Voutilainen, M.H., Bäck, S., Pörsti, E., Toppinen, L., Lindgren, L., Lindholm, P., Peränen, J., Saarma, M*. and Tuominen, R. K. (2009) Neurotrophic factor MANF is neurorestorative in rat model of Parkinson’s disease . J Neurosci, 29: 9651-9659.

8. Palgi, M., R. Lindström, J. Peränen, T. P. Piepponen, M. Saarma, and T. I. Heino. (2009) Evidence that DmMANF is an invertebrate neurotrophic factor supporting dopaminergic neurons. Proc. Natl. Acad. Sci. U.S.A. 106:2429-2434.

9. Parkash, V., P. Lindholm, J. Peränen, N. Kalkkinen, E. Oksanen, M. Saarma, V. M. Leppänen, and A. Goldman. (2009) The structure of the conserved neurotrophic factors MANF and CDNF explains why they are bifunctional. Protein Eng. Des. Sel. 22:233-241.

10. Hellman M, Arumäe U,  Yu L-Y, Lindholm P, Peränen J, Saarma M and Permi P. (2011) Neurotrophic factor MANF has a unique mechanism to rescue apoptotic neurons. J. Biol. Chem. 286: 2675-2680.

11. Apostolou A, Shen Y, Liang Y, Luo J, Fang S. Armet, a UPR-upregulated protein, inhibits cell proliferation and ER stress-induced cell death. Experimental Cell Research 314, 2454-2467 (2008).

12. Lindahl, M., Danilova, T., Palm, E., Lindholm, P., Võikar, V., Hakonen, E., Ustinov, J., Andressoo, J-O., Harvey, B.K., Otonkoski, T., Rossi, J. and Saarma, M (2014) MANF is indispensable for the proliferation and survival of pancreatic b-cells. Cell Reports 7: 366-75