A single glycoprotein on the surface of growing nerve cells may act as a master switch that amplifies the signals of all four major nerve growth factors, potentially offering a new way to treat neurodegenerative diseases like Alzheimer’s. Current treatments that deliver these growth factors directly have failed in the clinic because the proteins break down too quickly and can trigger cell death instead of repair. The glycoprotein, neuropilin-1 (NRP1), is already known to enhance growth factor signalling in blood vessels, but its role in the brain has been overlooked. This project will test whether NRP1 binds to each of the four neurotrophins—NGF, BDNF, NT-3, and NT-4—and to their receptors, and whether it boosts their ability to promote neuron growth and survival. If NRP1 proves to be a universal co-receptor for neurotrophins, it could become a therapeutic target for stimulating nerve regeneration after injury or in degenerative disease. The work is fundamental science—it asks how a molecule discovered in blood vessels actually works in the brain—but understanding this mechanism could open the door to drugs that reinnervate damaged brain tissue, something no current therapy can achieve.
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Neurodegenerative diseases, such as Alzheimer’s disease, involve a decrease in the ‘neurotrophic’ growth factors responsible for neuronal growth. This family of four growth factors - nerve growth factor (NGF), brain-derived growth factor (BDNF), neurotrophin-3 (NT-3) and neurotrophin-4 (NT-4) - act through cell-surface receptor tyrosine kinases (RTKs). Administering neurotrophins to trigger neuronal growth have had limited clinical benefit, attributed to the short half-life of neurotrophins and the opposing actions of known ‘pro-death’ co-receptor, p75NTR. Neuropilin-1 (NRP1) is a glycoprotein also localised to the sprouting tips of these developing neurons. NRP1 is known for its role in blood vessel development by enhancing how growth factors signal, however it was first discovered for its role in neuronal development. Our previous work found that NRP1 directly interacts with NGF and regulates pain. This has not been explored with respect to neurodegeneration. Interestingly, other members of neurotrophin family possess this prospective NRP1-binding motif. This award aims to explore the role of NRP1 in neurotrophin-mediated neuronal development, testing the hypothesis that NRP1 is a co-receptor regulating neurotrophic signalling across NGF, BDNF, NT-3 and NT-4. To address this, we will assess whether NRP1 interacts with (i) the growth factors themselves, (ii) the receptors through which they signal, and/or (iii) whether this glycoprotein affects neurotrophin-mediated neuronal development. NRP1 could be a novel modulator upregulating signalling across the neurotrophin family, as a key therapeutic target to promote neuronal development. Exploring mechanisms to reinnervate the brain following neuronal death would identify therapeutic avenues for treating, and even reversing, neurodegenerative disease.
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