Gene expression analysis of Drosophila Manf mutants reveals perturbations in membrane traffic and major metabolic changes

Abstract

BackgroundMANF and CDNF are evolutionarily conserved neurotrophic factors that specifically support dopaminergic neurons. To date, the receptors and signalling pathways of this novel MANF/CDNF family have remained unknown. Independent studies have showed upregulation of MANF by unfolded protein response (UPR). To enlighten the role of MANF in multicellular organism development we carried out a microarray-based analysis of the transcriptional changes induced by the loss and overexpression of Drosophila Manf.ResultsThe most dramatic change of expression was observed with genes coding membrane transport proteins and genes related to metabolism. When evaluating in parallel the ultrastructural data and transcriptome changes of maternal/zygotic and only zygotic Manf mutants, the endoplasmic reticulum (ER) stress and membrane traffic alterations were evident. In Drosophila Manf mutants the expression of several genes involved in Parkinson's disease (PD) was altered as well.ConclusionsWe conclude that besides a neurotrophic factor, Manf is an important cellular survival factor needed to overcome the UPR especially in tissues with high secretory function. In the absence of Manf, the expression of genes involved in membrane transport, particularly exocytosis and endosomal recycling pathway was altered. In neurodegenerative diseases, such as PD, correct protein folding and proteasome function as well as neurotransmitter synthesis and uptake are crucial for the survival of neurons. The degeneration of dopaminergic neurons is the hallmark for PD and our work provides a clue on the mechanisms by which the novel neurotrophic factor MANF protects these neurons.

The Good, the Bad, and the Toxic: Approaching Hormesis in Daphnia magna Exposed to an Energetic Compound

“…This family is evolutionary well conserved among multicellular organisms 22,23 . Recent studies in Drosophila suggest the involvement of manf in metabolism, membrane transport and transporters, oxidative phosphorylation, mitochondrial function, and protein ubiquitination, which is consistent with some of the effects detected in Daphnia by functional analysis 24 .…”

Mesencephalic Astrocyte-derived Neurotrophic Factor (MANF) Secretion and Cell Surface Binding Are Modulated by KDEL Receptors

“…It is possible that the interaction between MANF and KDELRs is tightly coupled to the secretory homeostasis of cells. Interestingly, a recent genomic study in Drosophila revealed perturbations in membrane trafficking in mutants lacking MANF, further implicating a potential role for MANF in protein trafficking pathways (40). In sum, our analyses demonstrate the importance of the C-terminal RTDL sequence in MANF trafficking and response to ER stress in neuronal cell types.…”

Mesencephalic astrocyte-derived neurotrophic factor reduces cell apoptosis via upregulating HSP70 in SHSY-5Y cells

“…In a whole-genome microarray and pathway analysis, the expression of genes involved in membrane transport and the ER stress was found to be altered, in the absence of MANF, in drosophilaa models [20]. In parallel with this study, our RNA-seq result revealed that many of the genes up-regulated in MANF treatment group were associated with biological processes/pathways related to stimulus response.…”