Now for some basic cell biology. I have read about the endoplasmic reticulum and Golgi apparatus several times now but it never seems to stick, so finally last night I had @K explain it to me, and am blogging about it now in the hopes of making it stick. With luck it may even connect to prions and FFI.
First off, only some proteins ever visit the ER and Golgi. The ER is an oxidative environment, similar to the (oxidative) extracellular matrix and unlike the reductive cytosol, so it’s a place to form, for instance, disulfide bonds which could not be formed in the cytosol. For proteins, such as PrP, which are headed for a transmembrane fate, they get translated directly into the ER. That is to say, ribosomes attach to the outside of the ER and translate an mRNA strand floating in the cytosol, directly spitting the translated amino acid chain into the ER. ER with ribosomes stuck to the outside appears “rough” in electron microscopy, so when people first saw it they named it “rough ER” as opposed to “smooth ER” without ribosomes.
Naturally, proteins born in the ER and destined for the extracellular environment cannot afford to ever encounter the cytosol in their lives, so they need a way to move around the cell insulated from the cytosol. Hence the concept of vesicular transport. When these proteins are done with their time in the ER, the ER actually buds off membrane-bound vesicles which maintain an oxidative environment on the inside, and these vesicles then carry the proteins to the Golgi apparatus. That’s a place where things like glycosylation (an important step for PrP) or for instance phosphorylation occur. Then they bud off into vesicles yet again and travel through the cytosol, finally merging with the cell membrane, making their insides become the outside of the membrane. (Conversely, sometimes the outside of the membrane buds inward creating a vesicle inside the cell which can then acidify on the inside to become a lysosome where waste materials are broken down).
Much of this biology is depicted beautifully in Inner Life of the Cell presented by Harvard’s Biovisions. The narrated version is much more educational but sadly lacks a digital timer, full-screen capability and embedability, so I’ll make reference to the new age music version someone has reposted on Youtube:
Here are some highlights:
- 1:59 – ribosomes translating proteins directly into the ER
- 2:05 – the budding off of membrane-bound vesicles from the ER
- 2:09 – the vesicles traveling from ER to Golgi
- 2:14 – the Golgi apparatus
- 2:21 – a vesicle fusing with the cellular membrane so that its inside becomes the outside surface of the cell
The ER is also responsible for the unfolded protein response. In response to stresses that make proteins unfold or misfold, the ER will take them in and either restore their function or, if it is unable to do so, initiate apoptosis.
When I first heard about this it seemed awfully relevant to PrP, since PrP both has this unfortunate tendency to misfold and has been identified as having anti-apoptotic properties. Apparently I’m not the only one to see a connection. A quick search revealed a couple of papers on the topic:
The theme of both of Soto’s papers seems to be that misfolded PrP causes ER stress and that this is what (or part of what) leads to neuronal dysfunction. Rane’s study provides some supporting evidence– if I grasp it correctly, they think that prion disease leads to ER stress which leads to excess PrP ending up in the cytosol, where it does not belong and is toxic; they try to demonstrate this by expressing a variant of PrP that has reduced translocation, i.e. it doesn’t make its way to the ER anyway, and showing that this variant is toxic.