Perna, A. | bioRxiv Science

bioRxiv2021

Translational control of polyamine metabolism by CNBP is required for Drosophila locomotor function

Microsatellite expansions of CCTG repeats in the CNBP gene leads to accumulation of toxic RNA and have been associated to DM2. However, it is still unclear whether the dystrophic phenotype is also linked to CNBP decrease, a conserved CCHC-type zinc finger RNA binding protein that regulates translation and is required for mammalian development. Here we show that depletion of Drosophila CNBP in muscles causes age-dependent locomotor defects that are correlated with impaired polyamine metabolism. We demonstrate that the levels of ornithine decarboxylase (ODC) and polyamines are significantly reduced upon dCNBP depletion. Of note, we show a reduction of the CNBP-polyamine axis in muscle from DM2 patients. Mechanistically, we provide evidence that dCNBP controls polyamine metabolism through binding dOdc mRNA and regulating its translation. Remarkably, the locomotor defect of dCNBP-deficient flies is rescued by either polyamine supplementation or dOdc1 overexpression. We suggest that this dCNBP function is evolutionarily conserved in vertebrates with relevant implications for CNBP-related pathophysiological conditions. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=195 SRC="FIGDIR/small/441910v2_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@a8c31corg.highwire.dtl.DTLVardef@1a18260org.highwire.dtl.DTLVardef@76a3d4org.highwire.dtl.DTLVardef@fdd041_HPS_FORMAT_FIGEXP M_FIG C_FIG CNBP controls muscle function by regulating the polyamine metabolism O_LILack of dCNBP impairs locomotor function through ODC-polyamine downregulation C_LIO_LIdCNBP binds dOdc mRNA and regulates its translation C_LIO_LIPolyamine supplementation or dOdc1 reconstitution rescues locomotor defects C_LIO_LICNBP-ODC-polyamine levels are reduced in muscle of DM2 patients C_LI

genetics↗

bioRxiv2021

Revealing Notch-dependencies in synaptic targets associated with Alzheimer's disease

Alzheimers disease (AD) is a progressive neurodegenerative disorder and the major cause of dementia. There is evidence that synaptic dysfunction and perturbation of Excitatory/Inhibitory (E/I) balance arise at the early stages of AD, altering the normal neural network activity, and leading to cognitive decline. Recent studies have identified Notch signaling as a contributor of neurodegenerative advancement including AD pathophysiology. As part of the efforts to understand molecular mechanisms and players involved in cognitive decline, we employed transgenic mouse models with Notch1 and RBPJK loss of function (LOF) in pyramidal neurons of the CA fields. Using bulk RNAseq. We have investigated the differential expression of Notch-dependent genes either upon environmental enrichment (EE) or upon Kainate injury (KA). We found a substantial genetic diversity in absence of both Notch1 receptor or Rbpjk transcriptional activator. Among differentially expressed genes, we observed a significant upregulation of Gabra2a in both knockout models, suggesting a role for Notch signaling in the modulation of E/I balance. Upon neuroexcitotoxic stimulation, loss of Rbpjk results in decreased expression of synaptic proteins with neuroprotective effects. We confirmed Nptx2, Npy, Pdch8, TncC as direct Notch1/Rbpjk targets and Bdnf and Scg2 as indirect targets. Finally, we translate these findings into human entorhinal cortex containing the hippocampal region from Alzheimers Disease patients performing targeted transcripts analysis. We observe an increased trend for Rbpjk and the ligand DNER but not Notch1 expression. On the other hand, neuron-specific targets, Nptx2, Npy, BDNF and Gabra2a are upregulated during the mild-moderate stage, and decline in the severe phase of the disease. These findings identify Notch as a promising signaling cascade to fine-tune in order to ameliorate synaptic transmission and memory deficits that occur during early phase of the Alzheimers Disease. HighlightsO_LILoss of canonical and/or non-canonical Notch1 signaling in pyramidal neurons of the hippocampal CA field mainly affects the post-synaptic compartment. C_LIO_LIIn both RBPJKcKO and Notch1cKO mouse models there is upregulation of GABAergic receptor subunit alpha2 (Gabra2a). C_LIO_LIThe plasticity genes: Npy, Nptx2,Pcdh8 and TncC with neuroprotective functions and known association with Alzheimers Disease are direct Notch/Rbpjk targets. C_LIO_LIDuring the mild-moderate stage of AD dementia, Notch canonical signaling promotes the expression of neuroprotective proteins, in the attempt of mitigating the effect of the excitatory-inhibitory imbalance. This activity is not observed during severe stages of the disease. C_LI

neuroscience↗