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Modulating brain structural plasticity versus neurodegeneration via a novel mechanism involving neurotrophins and dopamine, Tolls and Kek truncated-Trk-like receptors in Drosophila.

Periodic Reporting for period 1 - TOLKEDA (Modulating brain structural plasticity versus neurodegeneration via a novel mechanism involving neurotrophins and dopamine, Tolls and Kek truncated-Trk-like receptors in Drosophila.)

Reporting period: 2018-09-01 to 2020-08-31

The brain changes through life: structural plasticity drives generation of neurites, neurons and synapses to adapt and learn, and their elimination maintains homeostasis, but causes neurodegeneration in ageing and disease. Neurotrophins promote neuronal survival and structural plasticity in the human brain, and neurodegenerative and psychiatric diseases are often linked to alterations in neurotrophins and the neuromodulator dopamine. However, progress linking the neurotrophin and dopaminergic systems has been slow due to the lack of a simpler genetic model organism. Furthermore, it is imperative to discover novel molecular pathways that can be targeted to treat brain disease. Here, we used a genetic context in the fruit-fly Drosophila to expedite discovery.

Drosophila neurotrophins (DNTs) are evolutionarily conserved, and like mammalian neurotrophins, they also promote neuronal survival, connectivity and synaptogenesis. However, there are no canonical neurotrophin p75 or TrK receptors in Drosophila, and DNTs bind Toll and kinase-less Trk-like Kekkon (Kek) receptors instead. Toll and Toll-Like Receptors (TLRs) in mammals are best known for their functions in innate immunity and inflammation, but the neuronal functions of TLRs have been little investigated. Keks are Trk-like receptors lacking the kinase domain, and in humans, kinase-less truncated TrkB receptors underlie psychiatric disorders. A non-canonical novel mechanism involving DNT2 binding a receptor complex formed of Toll-6 and Kek-6 regulating neurite growth and synaptogenesis could potentially be conserved also in humans.

In this project, the Researcher Jun Sun supervised by Scientist in Charge Professor Alicia Hidalgo carried out the following research objectives (ROs):

ROI: To create a map of DNT2, Toll-6, Kek-6 and dopaminergic neurons in the adult brain, using gene editing technology and neural circuit registration.
RO2: To test whether altering the functions of DNT2, Toll-6 and Kek-6 affects the dopaminergic system, and whether this is linked to behavioural deficits and neuronal activity.
RO3: To test whether manipulating the DNT2/Toll-6/Kek-6 signalling module in the dopaminergic system can promote neuroprotection in a Drosophila model of Parkinson's disease.
Work was carried to target each RO and results have been obtained meeting the ROs, as follows:

RO1: DNT2, Toll-6 and Kek-6 were mapped within dopaminergic-related neuronal circuits. Using a combination of MCFO clones, reporter lines, NBLAST registration and comparisons to RNAseq databases, we identified the expressing cells and their relationship to the dopaminergic system.
RO2: using a combination of mutants, conditional knock-down and over-expression in the adult, we characterised the effect of altering levels of DNT2, Toll-6 and KeK-6 on neuronal structure. Furthermore, we characterized the effects on behavior.
RO3: using genetic technology and conditional over-expression, we described the functional relationship between the dopaminergic and DNT system and the ability of DNT2 to promote neuroprotection in Drosophila.

To conclude, we have shown that a novel mechanism involving neurotrophins with non-canonical Trk and Toll receptors regulates the dopaminergic system. Our findings will have important implications for understanding human brain health and disease, most particularly neurodegenerative diseases such as Parkinson’s disease and psychiatric disorders, both of which involve the dopaminergic system.
This project resulted in the following impacts:

1 Dissemination of knowledge for the benefit of scientific progress, and that of other researchers in the broader neuroscience community, in the form of presentation of our findings at scientific conferences in 2020 and 2021 (e.g. FENS, NeuroFly).

2 Publication of findings in peer-reviewed scientific journals.

Harrison N, Connolly E, Gascon Gubieda A, Yang Z, Altenhein B, Losada-Perez M, Moreira M, Sun J, Hidalgo A (2021) Regenerative neurogenic response from glia requires insulin driven neuron-glia communication. eLife 10: e58756.

Manuscript in preparation:

Sun J, Ulian-Benitez S, Cachero S, Kavanagh D, Forero M, Moreira M, Jefferis G and Hidalgo A. (in preparation) Structural plasticity of a dopaminergic circuit regulated by a neurotrophin via a Toll and kinase-free Trk receptor.. To be submitted for publication and our findings will also be made public through Europe PMC and UBIRA (University of Birmingham).

3 Public Engagement with Research: we communicate the importance of our work to the general public by participating in international Brain Awareness Week (2019, 2021) , Museum Lates at the Think-Tank Science Museum Birmingham and similar events.

4 In the longer term, our findings will have an impact in improving human brain health. The relevance of research carried out using Drosophila has been recognized by six Nobel Prizes and has recurrently resulted in discoveries of great importance for human health. Our findings will have an impact in understanding brain disease and meeting the EU Priorities of tackling aging and neurodegenerative diseases within the 3rd Health Programme.

5 The Researcher and Scientist in Charge will remain in contact and willingly collaborate, thus increasing the quality and international science, and of both UK and China. Our project also engaged a collaborator in Colombia, thus also impacting on the scientific outputs of this South-American country.



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Dopaminergic neurons in Drosophila brain - Sun & Hidalgo