Browsing by Subject "biologia, molekyyli- ja solubiologia, neurobiologia"

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  • Palgi, Mari (Helsingin yliopisto, 2012)
    Among neurotrophic factors MANF/CDNF family is unique as their protein sequences are evolutionarily conserved between multicellular organisms. Still, little is known about their mechanism of action and interacting molecules. At the time of initiation of this study there were no known neurotrophic factors in invertebrates. According to the protein sequence homology there was an uncharacterized homologue to the novel neurotrophic factor MANF in Drosophila melanogaster. We found that Drosophila Manf (DmManf) is an essential gene in a fruit fly development. DmManf represents a true orthologue to mammalian MANF as its mutant lethality is rescued by human MANF. We have generated DmManf deletion mutant surviving to second instar larval stage with maternal contribution. When the maternal contribution of DmManf is abolished, the mutants die at the end of embryogenesis before hatching. In DmManf mutant the dopaminergic neurites degenerate and the dopamine level is extremely low. Ultrastructural analysis reveals nonapoptotic cell death in the embryonic ventral nerve cord and neuropile decomposition together with cell body glia activation taking place. In secretory cells like gastric caeca or fat body the visible loss of rough endoplasmic reticulum and drastic accumulation of vesicles, some filled with cellular debris, occur. According to microarray expression analysis data, expression of genes involved in vesicular transport and metabolism were altered in DmManf mutants. The expression of several genes implicated in pathology of Parkinson s disease (PD) was also altered. The degeneration of dopaminergic neurons is the hallmark for PD and this thesis work makes an effort to enlighten the mechanisms how the neurotrophic factor MANF protects these degenerating neurons.