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

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

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.

Data: CORDIS, © European Union