Vesicular Glycolysis Provides On-Board Energy for Fast Axonal Transport is an elegant paper that was published just recently in Cell. It quite effectively solves a really puzzling aspect of how nerves work that until now made absolutely no sense and has really cool implications for better understanding – and thus hopefully better treating – Huntington’s disease. Here is a video where the authors present their paper:
Frédéric Saudou and colleagues explain why the glycolytic enzymes GAPDH and PGK are present on axonal vesicles: to provide a steady energy source that supplies the ATP necessary for fast axonal transport.
Here is the paper itself with its abstract:
D Zala, MV Hinckelmann, Hua Yu, et al. Published 2013 in Cell. http://dx.doi.org/10.1016/j.cell.2012.12.029
Fast axonal transport (FAT) requires consistent energy over long distances to fuel the molecular motors that transport vesicles. We demonstrate that glycolysis provides ATP for the FAT of vesicles. Although inhibiting ATP production from mitochondria did not affect vesicles motility, pharmacological or genetic inhibition of the glycolytic enzyme GAPDH reduced transport in cultured neurons and in Drosophila larvae. GAPDH localizes on vesicles via a huntingtin-dependent mechanism and is transported on fast-moving vesicles within axons. Purified motile vesicles showed GAPDH enzymatic activity and produced ATP. Finally, we show that vesicular GAPDH is necessary and sufficient to provide on-board energy for fast vesicular transport. Although detaching GAPDH from vesicles reduced transport, targeting GAPDH to vesicles was sufficient to promote FAT in GAPDH deficient neurons. This specifically localized glycolytic machinery may supply constant energy, independent of mitochondria, for the processive movement of vesicles over long distances in axons.
In human cells we have two kinds of ways to generate Adenosine Triphosphate (ATP), one of the basic energy storing molecules in the cell that is the immediate source of energy for most things that require power. The most basic way to make ATP is substrate level phosphorylation, where chemical reactions that break down molecules with high potential chemical energy (like glucose) are directly coupled to a second reaction that shoves a phosphate onto Adenosine Monophosphate or Adenosine Diphosphate using that same energy. Our cells do this naturally as they break down glucose into pyruvate that can be put through the Krebs Cycle, which leads to the real source of most of the energy of our cells, oxidative phosphorylation in our mitochondria. You can see a gorgeous video of the process here:
Be sure to also check out this video that explains what is going on there
I’m not going to spend so much time on this second more complex process though, because it is a total red herring to what it turns out is going on here in this case specifically. Our neurons must transport chemical and protein cargoes from the main body of the cell to their more distant ends along axons in order for those distant ends to be able to function, but the distances involved (up to a meter in the case of some motor neurons) are orders of magnitude way to big for just passive diffusion to do the job. We already knew that neurons get around this problem with a well characterized type of active transport that uses vesicles pulled along microtubules by walking motor proteins, however we also knew that this process requires a heck of a lot of ATP and it was unclear where that was all coming from.
A Motor protein doing its thing
Until this paper we had always assumed the ATP was probably being produced by the mitochondria that we knew were roughly scattered about axons through the much more efficient oxidative phosphorylation pathway, but we also knew that those mitochondria were too widely spaced to be able to serve as a primary source of energy. Indeed, if that were the case it would have led to vesicles bunching up in dead spots that were too far from a mitochondria for enough ATP to diffuse to, which could not possibly work! These authors have now shown that a known ATP producing protein involved in glycolysis, GAPDH, is hooked onto vesicles as they travel and that it is both necessary and sufficient for their movement – elegantly sorting out the question. However, in addition to figuring out this basic mystery in a really cool way, they have also shown that the protein Huntingtin works as the scaffolding that holds the GAPDH onto the vesicle, which has the potential to be totally game changing in our understanding of how Huntington’s disease works.
We have known since the early 90s that Huntington’s, a particularly awful neurodegenerative disorder that leads to cognitive decline and affects muscle coordination that only really becomes noticeable after middle age, is caused by having at least one faulty copy of the Huntingtin gene. However, aside from having some shadowy guesses at a couple dozen other proteins Huntingtin interacts with, it has been unclear what exactly Huntingtin does in the cell that makes having two functioning copies of it so essential. This research is particularly exciting as it seems to provide the foundation for a model of a primary function of Huntingtin that could neatly explain how its dysfunction causes Huntington’s. If they and others can sort such a model out, demonstrating relevance, it could very easily lead to real treatments guided by the better understanding it would provide.
This paper also indirectly makes an excellent case for why funding basic research into those questions that stick in the backs of researchers minds, but are merely interesting with no apparent applications for the answers, really is incredibly important.