Novel Neurotrophic Factors for Mammals and Invertebrates
Principal Investigator: MART SAARMA
Researcher: Päivi Lindholm
Institute of Biotechnology, University of Helsinki
Parkinson's disease is a neurodegenerative disorder, which is characterized by gradual loss of dopamine producing neurons in the brain, most prominently in the substantia nigra. Neurotrophic factors are small secretory proteins that promote survival, differentiation and maintenance of neurons in developing and adult nervous system. The most potent and specific neurotrophic factor for dopaminergic neurons described so far is the glial cell line-derived neurotrophic factor (GDNF). We have found and characterized a novel conserved dopamine neurotrophic factor CDNF as a survival factor for dopaminergic neurons. CDNF and its earlier described homolog the mesencephalic astrocyte-derived neurotrophic factor MANF are secreted proteins with eight conserved cysteine residues, suggesting a unique protein fold and defining a novel MANF protein family. CDNF and MANF are widely expressed during embryonic and postnatal development of several tissues in mouse, including the brain, and they possess a specific survival promoting activity for mouse midbrain dopaminergic neurons in vitro. In a rat in vivo model of Parkinson's disease CDNF had a neuroprotective effect: CDNF prevented the 6-hydroxydopamine (6-OHDA)-induced degeneration of dopaminergic neurons and reduced behavioral impairment in these animals as efficiently as GDNF. Our results suggest that the novel factor CDNF might be beneficial for the treatment of Parkinson's disease. Our research is aimed to further characterize the role of CDNF and MANF proteins in the mammalian nervous system. We collaborate with Dr. Tapio Heino's group to understand the biological role of MANF family proteins in invertebrates.
Contact: mart.saarma(at)helsinki.fi, tel. +358 50 5002 726
Novel Neurotrophic Factors for Mammals and Invertebrates
Principal Investigator: TAPIO HEINO
Researcer: Mari Palgi
Institute of Biotechnology and Department of Biological and Environmental Sciences, University of Helsinki
Neurotrophic factors are small secretory proteins that by binding to their cognate receptors regulate the number of neurons in a given population, neurite branching and synaptogenesis, adult synaptic plasticity and maturation of neuronal phenotype. The mechanism how neurotrophic factors regulate the development and maintenance of neurons in the peripheral nervous system (PNS) is well characterized, but very little is known about their roles in the development and physiology of the central nervous system (CNS).
Paradoxically, until now, homologs of vertebrate neurotrophic factors have not been identified in invertebrate animals such as Drosophila. Taking into account the expression patterns and biological effects of known neurotrophic factors, it is clear that several new still uncharacterised factors should exist. Recently, a novel small family of neurotrophic factors, consisting of two closely related members, MANF and CDNF, have been isolated from vertebrates. We have isolated the Drosophila MANF gene, DmMANF, which encodes a protein highly similar to both MANF and CDNF.
In Drosophila DmMANF is expressed in embryonic CNS. We have created DmMANF mutants, which have serious abnormalities in the development of the CNS. Our experiments have also shown that DmMANF gene is required in the dopamine synthesizing cells of Drosophila. The lethality of DmMANF mutants can be rescued with DmMANF and also with human MANF transgenic constructs. This shows that the human and fly genes are orthologous and that we can use the powerful Drosophila genetics and methodology to study the function and interacting partners of this novel molecule.
Our future experiments are directed towards deeper understanding about the mode of DmMANF action, to identify the MANF receptors and target genes using genetic and biochemical approaches. Our research is conducted in close collaboration with the group of Prof. Mart Saarma (Institute of Biotechnology), who are studying the mammalian MANFs.
Contact: tapio.heino(at)helsinki.fi, tel. +358 9 1915 9049 or +358 9 1915 9590