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bioRxiv · 10.1101/2020.10.22.349928

Fragile X Premutation rCGG Repeats Impairs Synaptic Growth and Synaptic Transmission at Drosophila larval Neuromuscular Junction

Bhat, S. A.·Yousuf, A.·Mushtaq, Z.·Kumar, V.·Qurashi, A.
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Abstract

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a progressive neurodegenerative disease manifesting in the premutation (PM) carriers of the FMR1 gene with alleles bearing 55-200 CGG repeats. The discovery of a broad spectrum of clinical and cell developmental abnormalities among PM carriers with or without FXTAS, and in model systems suggests that neurodegeneration seen in FXTAS could be the inevitable end-result of pathophysiological processes set during early development. Hence, it is imperative to trace early pathological abnormalities. Our previous studies have shown that transgenic Drosophila carrying human-derived fragile X premutation-length CGG repeats are sufficient to cause neurodegeneration. Here, we used the same transgenic Drosophila model to understand the effects of fragile X premutation-length CGG repeats on the structure and function of the developing nervous system. We show that presynaptic expression of the premutation length CGG repeats restricts synaptic growth, reduces the number of synaptic boutons, leads to aberrant presynaptic varicosities, and impairs synaptic transmission at the larval neuromuscular junctions (NMJs). The postsynaptic analysis shows both glutamate receptor and subsynaptic reticulum proteins are normal. However, a high percentage of boutons show the reduced density of Bruchpilot protein, a key component of presynaptic active zones required for vesicle release. The electrophysiological analysis shows a significant reduction in the quantal content, a measure of total synaptic vesicles released per excitation potential. Together these findings endorse that synapse perturbation caused by rCGG repeats mediate presynaptically during larval NMJ development.

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Bhat, S. A., Yousuf, A., Mushtaq, Z., Kumar, V., Qurashi, A.. 2020-10-22. Fragile X Premutation rCGG Repeats Impairs Synaptic Growth and Synaptic Transmission at Drosophila larval Neuromuscular Junction. https://doi.org/10.1101/2020.10.22.349928

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