CDNF and MANF in Parkinson's Disease

In Parkinson’s disease (PD) dopamine (DA) neurons located in the substantia nigra (SN) degenerate and die. Since all current therapies only treat symptoms, we hope to develop novel disease-modifying therapies for PD. However, the results of GDNF phase II clinical trials with PD patients have yielded controversial results. Our group has discovered a new endoplasmic reticulum (ER) located neurotrophic factor (NTF) — cerebral dopamine neurotrophic factor (CDNF) [1-6] — that is homologous to mammalian MANF protein [7]. A single CDNF-MANF homologue gene is also found in invertebrate animals, such as D. melanogaster, where it is needed for the maintenance of dopaminergic neurites and dopamine levels in the fly. Thus, the MANF of Drosophila is a functional orthologue of human MANF and CDNF [8].

In collaboration with Prof. Raimo Tuominen’s and Prof. Barry Hoffer’s groups we have shown that striatal delivery of CDNF protects midbrain DA neurons and restores their function in a rat 6-hydroxydopamine (6-OHDA) model [6,9] and in a mouse MPTP model [10] of PD in vivo. We were the first to demonstrate that, similar to CDNF, MANF shows protective effects on dopaminergic neurons in a rat 6-OHDA model of PD [11]. Based on our rodent studies, we tested the efficacy of CDNF in two non-human species models of PD. First, we demonstrated the therapeutic effect of CDNF in a unilateral 6-OHDA lesion model of Parkinson's disease in marmoset monkeys [12]. Second, in collaboration with Prof. Judy L. Cameron’s group, we have found that in a rhesus monkey MPTP model of PD, CDNF protects and repairs dopamine neurons and regulates ER stress more efficiently than GDNF (Cameron, Saarma, unpublished).

The mechanism of action of CDNF and MANF remains poorly understood. Our results show that, when applied to the brain as a protein, CDNF acts like the ‘conventional’ NTFs promoting cell survival and functional recovery of midbrain circuits. However, in contrast to other NTFs, CDNF regulates ER stress and unfolded protein response (UPR) pathways [13], as well as the levels of pro-inflammatory cytokines [14]. In 2017, in three medical centers in Sweden and Finland, Herantis Pharma Plc commenced a first-in-human, phase I-II clinical study in 18 patients with PD. In this clinical study, CDNF will be administered directly into the brains of the patients using a device specially designed for such a procedure.

To understand the role of CDNF and MANF in mammals, we created CDNF and MANF knock-out mice [15]. Preliminary data demonstrate that CDNF-deficient mice have a normal life-span, but surprisingly develop age-dependent defects in the nervous system, similar to early stage PD patients. In collaboration with Dr. Mikko Airavaara, we are investigating the effects of CDNF in α-synuclein models of PD, and with Dr. Merja H. Voutilainen, we are searching for new delivery modes for CDNF.

References:

  1. Lindholm P, Saarma M. (2010) Novel CDNF/MANF family of neurotrophic factors, Dev Neurobiol. 70:360-371. 10.1002/dneu.20760
  2. Voutilainen MH, Arumäe U, Airavaara M, Saarma M. (2015) Therapeutic potential of the endoplasmic reticulum located and secreted CDNF/MANF family of neurotrophic factors in Parkinson's disease. FEBS Lett. 589 (2015) 3739–3748. 10.1016/j.febslet.2015.09.031
  3. Lindahl M, Saarma, M and Lindholm P (2017) Unconventional neurotrophic factors CDNF and MANF: Structure, physiological functions and therapeutic potential. Neurobiology of Disease 97, 90–102. 10.1016/j.nbd.2016.07.009
  4. Lindholm D, Mäkelä J, Di Liberto V, Mudò G, Belluardo N, Eriksson O, Saarma M. (2016) Current disease modifying approaches to treat Parkinson's disease.Cell Mol Life Sci. 73(7):1365-1379. doi: 10.1007/s00018-015-2101-1. 10.1007/s00018-015-2101-1
  5. Saarma M, Laurén J, Lindholm P, Timmusk T and Tuominen RK. Neurotrophic factor protein and uses thereof. Patent US 7,452,969.
  6. 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. 10.1038/nature05957
  7. 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.
  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. 10.1073/pnas.0810996106
  9. 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. 10.1016/j.expneurol.2010.12.013
  10. 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.  10.3727/096368911X600948
  11. 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. 10.1523/JNEUROSCI.0833-09.2009
  12. Garea-Rodríguez E, Eesmaa A, Lindholm P, Schlumbohm C, König J, Meller B, Krieglstein K, Helms G, Saarma M, Fuchs E. (2016) Comparative Analysis of the Effects of Neurotrophic Factors CDNF and GDNF in a Nonhuman Primate Model of Parkinson's Disease. PLoS One. 2016 Feb 22;11(2):e0149776. 10.1371/journal.pone.0149776
  13. Voutilainen  MH, De Lorenzo F, Stepanova P, Bäck S, Yu L-y, Lindholm P., Pörsti E, Saarma M, Männistö P, Tuominen RK. (2017) Evidence for an additive neurorestorative effect of simultaneously administered CDNF and GDNF in hemiparkinsonian rats: implications for different mechanism of action. eNeuro, Mar 13;4(1). 10.1523/ENEURO.0117-16.2017
  14. Nadella R, Voutilainen MH, Saarma M, Gonzalez-Barrios JA, Leon-Chavez BA, Jiménez JM, Jiménez SH, Escobedo L, Martinez-Fong D. (2014) Transient transfection of human CDNF gene reduces the 6-hydroxydopamine-induced neuroinflammation in the rat substantia nigra. J Neuroinflammation. 11(1):209. 10.1186/s12974-014-0209-0
  15. 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 10.1016/j.celrep.2014.03.023