Biology subjects

Georgii, E.

Publications and source records attributed to Georgii, E..

4 recordsLinked to original sources

bioRxiv2025

Formation of amyloid-like HTTex1 aggregates in neurons, downregulation of synaptic proteins and early mortality of Huntington's disease flies are causally linked

Amyloidogenic mutant huntingtin exon-1 (mHTTex1) protein aggregates with pathogenic polyglutamine (polyQ) tracts are the potential root cause of Huntingtons disease (HD). Here, we assessed the gain-of-function toxicity of mHTTex1 aggregation in neurons of HD transgenic flies. We show that the rate of mHTTex1 aggregation in neurons and early mortality of HD transgenic flies are correlated. We observed sequestration of key synaptic proteins into amyloid-like mHTTex1 aggregates and a concomitant decrease of their transcript levels, suggesting that progressive mHTTex1 aggregate stress in neurons leads to an impairment of synaptic function. Machine learning-based data analysis revealed that the abundance of synaptic proteins such as the vesicular monoamine transporter Vmat in the brain is predictive of fly survival. RNAi knockdown of Vmat-encoding transcripts in neurons with pathogenic amyloid-like HTTex1Q97 aggregates further shortened the lifespan of HD flies, supporting the hypothesis that mHTTex1 aggregation drives impairment of synaptic processes and pathogenesis of HD.

molecular biology↗

bioRxiv2023

miR-7 controls glutamatergic transmission and neuronal connectivity in a Cdr1as-dependent manner

The circular RNA (circRNA) Cdr1as is conserved across mammals and highly expressed in neurons, where it directly interacts with microRNA miR-7. However, the biological function of this interaction is unknown. Here, using primary forebrain murine neurons, we demonstrate that stimulating neurons by sustained depolarization rapidly induced two-fold transcriptional up-regulation of Cdr1as and strong post-transcriptional stabilization of miR-7. Cdr1as loss caused doubling of glutamate release from stimulated synapses and increased frequency and duration of local neuronal bursts. Moreover, periodicity of neuronal networks was increased and synchronicity was impaired. Strikingly, these effects were reverted by sustained expression of miR-7 which also cleared Cdr1as molecules from neuronal projections. Consistently, without Cdr1as, transcriptomic changes caused by miR-7 overexpression were stronger (including miR-7-targets down-regulation) and enriched in secretion/synaptic plasticity pathways. Altogether, our results suggest that in forebrain neurons Cdr1as buffers miR-7 activity to control glutamatergic excitatory transmission and neuronal connectivity important for long-lasting synaptic adaptations.

molecular biology↗

bioRxiv2020

A fine-tuned interplay of three A. thaliana UDP glucosyltransferases orchestrates salicylic acid homeostasis

Salicylic acid (SA) is a central signaling molecule in development and defense, therefore its levels are tightly controlled. One control mechanism is conjugation with sugar moieties by UDP glucosyltransferases (UGTs). In Arabidopsis, UGT76B1, UGT74F1, and UGT74F2 are known to glucosylate SA. We show that these are the main SA UGTs in leaves, since only marginal levels of SA glucosides were found in a triple loss-of-function mutant. Analyzing transcriptomes, metabolite levels, and phenotypes of a full combinatorial set of loss-of-function mutants, we resolved the mutual relationships and the individual roles of these enzymes in SA homeostasis. The strongest gene expression changes were observed for the ugt76b1 ugt74f1 double mutant, which downregulated developmental genes and most pronouncedly upregulated cell death-related genes. Among the single mutants, ugt76b1 specifically exhibited increased production of reactive oxygen species, increased resistance to infection, and early senescence. Likewise, higher-order mutations confirmed the dominant role of UGT76B1 in controlling SA levels and thereby the expression of biotic stress response genes. Both UGT74F1 and UGT74F2 affected UGT76B1 expression. However, while UGT76B1 and UGT74F1 produced SA-2-O-{beta}-glucoside, UGT74F2 did not contribute there substantially. Instead, UGT74F2 acted independently of UGT74F1, decreasing steady-state SA levels by producing salicyloyl glucose ester. Remarkably, this did not restrict defense responses. In contrast, UGT74F1 interacted with UGT76B1 in suppressing defense responses. Nevertheless, a benzothiadiazole-triggered defense scenario induced only UGT76B1, whereas UGT74F1 was linked to controlling abiotic stress responses. All three enzymes form a network that, in concert with other UGTs, regulates expression of developmental and stress-related genes. One sentence summaryThe salicylic acid glucosylating enzymes of Arabidopsis leaves are crucial for salicylic acid homeostasis and combinatorially impact defense responses and developmental processes.

plant biology↗

bioRxiv2020

Nitric oxide coordinates histone acetylation and expression of genes involved in growth/development and stress response

Nitric oxide (NO) is a signaling molecule with multiple regulatory functions in plant physiology and stress response. Besides direct effects on the transcriptional machinery, NO can fulfill its signaling function via epigenetic mechanisms. We report that light intensity-dependent changes in NO correlate with changes in global histone acetylation (H3, H3K9 and H3K9/K14) in Arabidopsis thaliana wild-type leaves and that this correlation depends on S-nitrosoglutathione reductase and histone deacetylase 6. The activity of histone deacetylase 6 was sensitive to NO, which demonstrates that NO participates in regulation of histone acetylation. ChIP-seq and RNA-seq analyses revealed that NO is involved in the metabolic switch from growth and development to stress response. This coordinating function of NO might be of special importance in adaptation to a changing environment and could therefore be a promising starting point to mitigating the negative effects of climate change on plant productivity.

plant biology↗