Modeling of axonal endoplasmic reticulum network by spastic paraplegia proteins

The way we move – from simple motions like reaching out to grab something, to playing the piano or dancing – is coordinated in our brain. These processes involve many regions and steps, in which nerve cells transport signals along projections known as axons. Axons rely on sophisticated ‘engineering’ to work properly over long distances and are vulnerable to diseases that disrupt their engineering. For example, in genetic diseases called ‘hereditary spastic paraplegias’, damages to the ‘distal’ end of axons – the end furthest from the nerve cell body – cause paralysis of the lower body. Axons have several internal structures that make sure everything works properly. One of these structures is the endoplasmic reticulum, which is a network of tubular membranes that runs lengthwise along the axon. It is known that spastic paraplegias are sometimes caused by mutations affecting proteins that help to build and shape the endoplasmic reticulum, for example, the proteins of the reticulon and REEP families. However, until now it was not known how the ER forms its network in the axons and if this is influenced by these proteins. To see whether reticulons and REEPs affect the shape of the endoplasmic reticulum, Yalcιn et al. used healthy fruit fly larvae, and genetically modified ones that lacked the proteins. The results show that in healthy flies, the tubular network runs continuously along the axons. When either reticulon or REEP proteins were removed, the distal axons contained less endoplasmic reticulum. In mutant fly larvae that lacked both protein families, the endoplasmic reticulum was more interrupted and contained more gaps than in normal larvae. Using high-magnification electron microscopy confirmed these findings, and showed that the tubules of the endoplasmic reticulum in mutant axons were larger, but fewer. A next step will be to test whether these mutations also affect how the axons work and communicate over long distances. A better knowledge of the role of the endoplasmic reticulum in axons will help us to understand how damages to it could affect hereditary spastic paraplegias and other degenerative conditions.