Shepherd, D., Newman, T., Mudher, A. and Lovestone, S.
Modelling tauopathies in Drosophila
Neurobiology of Aging, 23, (1, Supplement 1), . (doi:10.1016/S0197-4580(02)00052-0).
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Tauopathies are a group of neurodegenerative diseases that are characterised by abnormalities in the microtubule associated protein Tau. Tau abnormalities in these tauopathies take the form of overexpression, hyperphosphorylation and aggregation into filaments which can accumulate to form the pathological hallmark of these diseases, the neurofibrillary tangles. Little is known about the mechanism(s) by which these Tau abnormalities evolve, and what affect they have on neuronal function. To analyse the cellular and molecular mechanisms underlying these defects, we have used Drosophila to model tauopathies. We have used the UAS/GAL4 expression system to selectively drive overexpression of human 0N3R Tau in either sensory neurones or motor neurones. In sensory neurons overexpression of Tau resulted in aberrations in sensory neuron morphology characterised by neuronal loss, abnormal fasciculation and blebbing of axons, and reduced aborisation 1. To extend thiswork we have overexpressed Tau in motor neurones. Tau expressing motor neurons display two characteristic defects. First, the structure of the neuromuscular junction exhibits a distinct hyperbranching phenotype, a phenomenon associated with synaptic dysfunction. Second overexpression of Tau leads to a disruption of axonal transport. In Tau overexpressing motor neurons the normal distribution of vesicles is disturbed and vesicles aggregate into large vesicular “clusters.” These data indicate that overexpression of Tau may adversely affect synaptic transmission and axonal transport. Collectively our data show that Drosophila can be used as a model organism to analyse the effects of Tau abnormalities and provide novel insight into the cellular and molecular mechanisms that underlie their pathogenesis. Furthermore, the powerful molecular genetics tools that Drosophila offers enable other aspects of the tauopathies to be investigated.
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