Drosophila as a model to understand the role of glial cells in neurodegeneration

Glial cells have evolved in close association with neurons in most sophisticated nervous systems and are essential for the development, proper functionality and maintenance of neuronal networks and of the whole nervous system. One of their key functions is to provide trophic support and buffering ability over time to neurons, which makes them a critical factor in homeostasis of the nervous system in ageing and for the onset and progression of neurodegenerative diseases.

Importantly for the 3Rs, because glial cell function is inevitably linked to that of its impact on neuronal cells and circuits, traditional cell culture approaches as a way or replacing animal experiments are less straightforward. As a consequence, virtually all information about glial cells in neurodegeneration has come from mouse studies.

We plan instead to to exploit our Drosophila model for dentatorubral-pallidoluysian atrophy (DRPLA) and a collection of microRNAs transgenic strains as a tool for discovery, to shed light on glial function and glia-neuron interactions in neurodegeneration, and as a solution for promoting replacement, and encouraging reduction, of animal experiments.

Our specific aims are:

1.To identify miRs and targeted genes of relevance in glia for polyglutamine neurodegeneration.
2.To identify miRs and targeted genes of relevance in neurons for polyglutamine neurodegeneration driven in glial cells.
3.To study the mechanism of action of the top miR(s)>genes network in glia-neuron interactions.

Although the paradigm we use is a rare human disease, our system is capable of identifying also general mechanisms that are relevant to any disease that involves glial malfunctioning and degeneration. In conclusion, in this project we will develop a research strategy of paramount importance for the 3R agenda, with a great potential for major findings in a key area of biomedical research, of proven interest to biotechnological and pharmacological industry.

Gonçalves-Pimentel C et al. (2020). A miRNA screen procedure identifies garz as an essential factor in adult glia functions and validates Drosophila as a beneficial 3Rs model to study glial functions and GBF1 biology. F1000Research 9:317. doi: 10.12688/f1000research.23154.1.

Mazaud D et al. (2019). Transcriptional Regulation of the Glutamate/GABA/Glutamine Cycle in Adult Glia Controls Motor Activity and Seizures in Drosophila. The Journal of Neuroscience  39(27):5269-5283. doi: 10.1523/JNEUROSCI.1833-18.2019

Napoletano F et al. (2019). Intersections between Regulated Cell Death and Autophagy. Trends in Cell Biology 29(4):323-338. doi: 10.1016/j.tcb.2018.12.007

Trébuchet G et al. (2019). The Repo Homeodomain Transcription Factor Suppresses Hematopoiesis in  and Preserves the Glial Fate. The Journal of Neuroscience 39(2):238-255. doi: 10.1523/JNEUROSCI.1059-18.2018

Baron O and Fanto M (2018). Karyoptosis: A novel type of cell death caused by chronic autophagy inhibition. Autophagy 14(4):722-723. doi: 10.1080/15548627.2018.1434372

Solomon D et al. (2018). A feedback loop between dipeptide-repeat protein, TDP-43 and karyopherin-α mediates C9orf72-related neurodegeneration. Brain 141(10):2908-2924. doi: 10.1093/brain/awy241

Baron O et al. (2017). Stall in Canonical Autophagy-Lysosome Pathways Prompts Nucleophagy-Based Nuclear Breakdown in Neurodegeneration. Current Biology 27(23):3626-3642.e6. doi: 10.1016/j.cub.2017.10.054

Joffre C et al. (2016). STK38 at the crossroad between autophagy and apoptosis. Autophagy 12(3):594-5. doi: 10.1080/15548627.2015.1135283

Joffre C et al. (2015). The pro-apoptotic STK38 kinase is a new beclin1 partner positively regulating autophagy. Current Biology 25(19):2479-92. doi: 10.1016/j.cub.2015.08.031

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Project grant

Status

Closed

Institution

King's College London

Grant reference number

NC/L000199/1

Award date

Feb 2014 - Feb 2017

Grant amount

£316,462