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Modelling of Axonal Endoplasmic Reticulum Network by Spastic Paraplegia Proteins

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Motor neurons control voluntary movements and have axons that can be up to 104 fold of the diameter of the cell body. Hence, motor neurons require complex machineries for maintenance and function over long axonal distances. Failure of these machineries causes motor neuron axonopathies, such as Hereditary Spastic Paraplegia (HSP), which is characterised by spasticity and weakness of the lower limbs. To date over 50 causative Spastic Paraplegia Genes (SPGs) have been identified, encoding a variety of proteins. Many of these proteins point at the importance of the endoplasmic reticulum (ER) for the function of motor neurons. Some of these protein families, including atlastin, spastin, reticulon, and REEP families, are involved in shaping ER tubules. To investigate the role of Spastic Paraplegia proteins in vivo, I first constructed tools for visualisation of ER in Drosophila axons. To understand the role of two proteins families, Reticulon and REEP , which share a partly redundant role in the formation of tubular ER in yeast, I investigated ER organisation in flies lacking these ER-shaping proteins. Loss of ReepA and ReepB (Drosophila orthologues of REE Ps1-4 and REE Ps 5-6 respectively), or of Rtnl1, caused ER abnormalities in epidermal cells. Ultrastructural evidence showed longer ER sheet cross-sections in larvae that lack ReepA and ReepB, suggesting an expansion of ER sheets. Loss of ReepA and ReepB, or of Rtnl1, lowered ER labelling in distal long motor axons. Strikingly, triple loss of Rtnl1, ReepA, and ReepB appeared to disrupt the continuity of axonal ER, and to cause fragmentation of ER in the middle parts of long motor neurons. Loss of Rtnl1 led to accumulations of synaptic vesicles in axons, suggesting an axon transport defect. These findings suggest that disruption of axonal ER could be an underlying reason for axonal degeneration in HSP . This is the first study to show that ER-shaping proteins can affect axonal structures, and maintain the integrity of axonal ER.

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