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.
Highlights
MANF and CDNF are evolutionarily conserved neurotrophic factors that support dopaminergic neurons
It might be due to the dissimilar roles of Manf gene during embryonic and larval stages or it indicates the difference between the absolute lack of Manf versus gradual diminishing of maternally contributed stores of Manf gene products
We found changed expression of several genes known to be associated with processes altered in Parkinson’s disease (PD) such as oxidative phosphorylation, mitochondrial function, dopamine metabolism and uptake, and protein ubiquitinaton
Summary
MANF and CDNF are evolutionarily conserved neurotrophic factors that support dopaminergic neurons. Independent studies have showed upregulation of MANF by unfolded protein response (UPR). Characterised MANF (Mesencephalic Astrocytederived Neurotrophic Factor) and CDNF (Cerebral Dopamine Neurotrophic Factor) form an independent family of neurotrophic factors [1]. MANF was identified from a conditioned media of cultured mesencephalic astrocytes in a search for secreted factors supporting dopamine (DA) neurons [2]. Specific loss of DA neurons is the characteristic feature of Parkinson’s disease (PD). ER stress and UPR have been implicated in the pathogenesis of several neurodegenerative diseases because of their characteristic accumulation of specific misfolded proteins [14]. Drosophila has been used progressively to model human neurodegenerative diseases and UPR [16,17,18]
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