Chair: Milena Damulewicz (Jagiellonian University, Cracow, Poland)

Symposium 14: Time for flies – an alternative model for research on brain diseases

The physiology of neurons is conserved and most of the cellular and molecular processes are similar among species. Hence, insects provide an excellent model for the investigation of human brain disorders. Drosophila melanogaster, thanks to the numerous transgenic strains available, provides genetic tools that facilitate neurobiological studies.


Milena Damulewicz, Institute of Zoology and Biomedical Research, Jagiellonian University, Cracow, Poland

Clock and brain health – important lesson from flies

Parkinson’s disease (PD) is one of the most common neurodegenerative disorder, caused by both genetical and environmental factors. Among the symptoms of PD are sleep problems, which affect quality of life and daytime functioning. Several lines of evidence suggest that one cause of sleep problems in patients with PD is circadian disfunction, which can accelerate the neurodegenerative process. However, the cellular mechanisms linking the circadian clock to neurodegeneration are still poorly understood. In this study we will show how PD progression affects clock functioning, and how clock disruption may enhance PD development.

References:
1. Szypulski K, et al. Autophagy as a new player in the regulation of clock neurons physiology of Drosophila melanogaster. Sci Rep. 2024. doi: 10.1038/s41598-024-56649-3
2. Doktór B, et al. Effects of MUL1 and PARKIN on the circadian clock, brain and behaviour in Drosophila Parkinson’s disease models. BMC Neurosci., 2019.
doi: 10.1186/s12868-019-0506-8


Aron Szabo, Biological Research Centre, Institute of Genetics, Szeged University, Szeged, Hungary

Glia-neuron interactions mediated by vesicular degradation pathways after traumatic nervous system injury in Drosophila

We are interested in membrane trafficking pathways in glia, especially phagocytosis, early damage signalling and their involvement in neuronal death. We take advantage of Drosophila as a genetically tractable model and inflict injuries using simple paradigms. We uncovered a role for glial LC3-associated phagocytosis in axon debris clearance1 and found elevated glial immunity in the absence of LAP. We deciphered how STAT TF activity is set during glial reactivity by degradation of a repressor2. We aim to understand the adaptive changes in glia elicited via such vesicular pathways in face of damage.

References:
1. Szabó Á, et al. LC3-associated phagocytosis promotes glial degradation of axon debris after injury in Drosophila models. Nat. Commun., 2023.
doi: 10.1038/s41467-023-38755-4
2. Vincze V, et al. Selective autophagy fine-tunes Stat92E activity by degrading Su(var)2-10/PIAS during glial injury signalling in Drosophila. bioRxiv, 2024.
doi: 10.1101/2024.08.28.610109


Aaron Voigt, Department of Neurology, RWTH Aachen University, Aachen, Germany

TRMT2A inhibition, a causative treatment of polyglutamine diseases? The path from basic fly science towards drug development

Genes linked to polyglutamine (polyQ) diseases like Huntington’s disease share expanded CAG stretches within the coding region, translated into expanded glutamine tracts in disease-linked proteins. These polyQ stretches are causative for disease. Due to their dominant inheritance and monogeneticity, diagnosis prior disease onset is common, but no cure is available so far. We show that inactivation of the tRNA-methyl transferase 2 homolog A (TRMT2A) suppresses polyQ-induced toxicity and aggregation in yeast, flies, HEK cells and mice. As loss of TRMT2A in analyzed organisms did not result in phenotypic abnormalities, inhibition of TRMT2A represents a therapeutic avenue to treat polyQ diseases.

References:
1. Witzenberger M, et al. Human TRMT2A methylates tRNA and contributes to translation fidelity. Nucleic Acids Res., 2023. doi: 10.1093/nar/gkad565
2. Voßfeldt H, et al. Large-scale screen for modifiers of ataxin-3-derived polyglutamine-induced toxicity in Drosophila. PLoS One., 2012.
doi: 10.1371/journal.pone.0047452


Sergio Casas-Tinto, Institute for Research of Rare Diseases, Carlos III Health Institute, Madrid, Spain

Stress shapes brain fitness in the progeny through epigenetic modifications

Glioblastoma is characterized by rapid proliferation, extensive invasiveness, and resistance to current therapeutic interventions. Despite similar genetic mutations, patients exhibit considerable heterogeneity in survival outcomes, ranging from weeks to years. This talk introduces a novel perspective on the interaction between the tumor and host, influenced by paternal environmental or lifestyle factors, termed the „brain fitness hypothesis.” Continuous light exposure induces oxidative stress in the brains of F1 progeny, which compromises brain fitness and accelerates tumor growth, leading to sex-dependent differences in life expectancy. Among the heritable mechanisms, miRNAs has emerged as a key mediator in the transmission of parental environmental exposure to subsequent generations, enhancing the propensity of glioblastoma cells to proliferate and extend tumor microtubes. Consequently, accelerated glioblastoma progression is driven by heritable risk factors acquired through stress exposure in the parental generation.

References:
1. Portela M, et al. Glioblastoma cells vampirize WNT from neurons and trigger a JNK/MMP signaling loop that enhances glioblastoma progression and neurodegeneration. PLoS Biol., 2019. doi: 10.1371/journal.pbio.3000545
2. Losada-Pérez M, et al. Synaptic components are required for glioblastoma progression in Drosophila. PLoS Genet., 2022 doi: 10.1371/journal.pgen.1010329

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