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Formation and disease relevance of axonal endoplasmic reticulum, a "neuron within a neuron”.

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If you have a question about this talk, please contact Caroline Newnham.

Axons contain a smooth tubular endoplasmic reticulum (ER) network that appears to be continuous with ER throughout the neuron. Its continuity is unique for intracellular membranous organelles and makes it potentially a channel for regional and long-distance communication in neurons, and it has been termed a “neuron within a neuron”.

The mechanisms that form this axonal ER network are unknown. Mutations affecting reticulon or REEP proteins, with intramembrane hairpin domains that model ER membranes, cause an axon degenerative disease, hereditary spastic paraplegia (HSP). We show that Drosophila axons have an extensive axonal ER network, which these proteins help to model. Loss of HSP hairpin proteins causes ER sheet expansion, partial loss of ER from distal motor axons, and occasional discontinuities in axonal ER. Ultrastructural analysis reveals an extensive ER network in axons, which shows larger and fewer tubules in larvae that lack reticulon and REEP proteins, consistent with loss of membrane curvature. Live imaging reveals an ER network with both stable and dynamic features, suggesting mechanisms that continually regulate its density and continuity.

Therefore HSP hairpin-containing proteins are required for shaping and continuity of axonal ER, thus suggesting roles for ER modeling in axon maintenance and function. A role for sporadic gaps in the ER network in HSP diseases is an attractive hypothesis for the susceptibility of longer axons to the disease, and identification of new HSP genes by human exome and genome sequencing may reveal additional components of the machinery that maintains ER organisation and function in axons. We have only scratched the surface of how axonal ER is formed, and its physiological function; a combination of human and Drosophila genetics promises to reveal more answers to these questions.

This talk is part of the Genetics Seminar series.

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