Scientists, especially geneticists, are often over-focused on the nucleus of a cell. After all, it holds the basic blueprints for all the gene products our cells make, right? Unfortunately, because the cell’s behaviors are so complex, sometimes it’s easy to over-focus on a single compartment (or even pathway) like the nucleus at the expense of remembering that the cell is a necessary gestalt and without its other constituent parts, life would go to hell and a hand basket.
One such example is the endoplasmic reticulum (ER), which lies just outside the nucleus and is vital in the production of many of our genes’ products. While the smooth endoplasmic reticulum (SER) helps to synthesize various fats (lipids) and carbohydrates used structurally and enzymatically in the cell, the rough endoplasmic reticulum (RER) is the location for protein production. The cell is made up of four basic organic molecules: DNA, proteins, lipids, and carbs. The ER is the location for the production of three out of four of those building blocks, making it an absolutely vital organelle.
The RER is not only the place where proteins are produced but the location where proteins go through a folding check to make sure that each one has taken on its appropriate shape. (In the molecular world, shape helps determine function.) If a protein is misfolded, it usually hooks up with a chaperone protein that helps it to fold properly before it’s allowed to leave the ER and go on its merry way. If the protein fails to fold properly, then it’s marked for disposal and goes through a process known as Endoplasmic Reticulum-associated Degradation (ERAD).
When you have a viral infection, the RER does a funny thing: it slows down the production of proteins. Why? Because the virus typically works by hijacking your cell’s machinery to do its bidding, and that means making viral proteins. This way, your infected cells slow the spread of the virus.
The same or very similar response is also used by the RER whenever a larger-than-usual number of proteins is misfolded and start to aggregate and gum up the works. This can be seen in conditions like Alzheimer’s and Huntington’s, in which misfolded proteins can form larger aggregates and inclusion bodies. Not only does the ER slow down protein translation to ease the flow and hopefully help itself catch back up again (kind of like playing a day of hookey to catch up on forgotten homework), but it also increases the number of chaperones available to help stem the backlog (like getting your friend to come over and help with your homework). If slowing down protein translation and increasing the available help doesn’t work, which may be the case if there’s an extreme backlog or the problem is occurring chronically, then pathways for apoptosis (cell death) are activated and the cell commits suicide. This is meant to be a protective mechanism known as the Unfolded Protein Response (UPR) intended to do away with sick cells, such as with infection or cancer. However, in people who have a propensity for protein aggregation, such as Alzheimer’s, this can lead to the death of very necessary cells and conditions such as neurodegeneration.
A neuronal plaque characteristic of Alzheimer’s.
Neuronal activity stimulates various forms of protein synthesis, in part in order to facilitate learning. Therefore, it probably comes as little surprise that seizures usually induce increased protein synthesis as well. Interestingly, if chemicals are used to slow down or prevent protein synthesis, cell death is less likely to occur following seizure activity . This suggests that seizures, probably through a variety of means, can trigger the UPR, increasing the likelihood that permanent cellular injury may occur since part of the UPR’s job is to trigger cell death if the number of folded proteins is too great or is chronically high .
Not only can epilepsy induce UPR, but UPR-related disorders also often have epilepsy as a feature. For instance, Congenital Disorders of Glycosylation (CDG) are a group of conditions in which epilepsy is a frequent feature. These conditions are defined by a failure to attach glycan carbohydrates to specific target proteins (glycoproteins), which results in defective protein folding and subsequent protein aggregation.
In fact, my step-grandson was the first patient diagnosed with a disorder of de-glycosylation (glycans fail to be removed from glycoproteins necessary for degradation) and he experiences many of the same features as CDG, including poorly-controlled seizures and delayed development. (If you’re interested in reading more about his family’s story, see The New Yorker article recounting their struggles and triumphs in finding a name for this mystery condition now known as NGLY1 Deficiency.)
In short, the ER is integral in sensing cell stress, is tightly attuned to the activities of the cell, including its other organelle partners like the mitochondria, and is key in directing what a cell should do in reaction to that stress, be it survive or suicide for the sake of the rest of the body. Scientists are now studying the ER’s involvement in many conditions today, both rare and common, including cardiovascular disease, neurodegeneration, diabetes, aging, and I’m even studying its potential roll in autism now. So while geneticists might get all hot-and-bothered over the nucleus of the cell and the importance of DNA and heredity, remember that the ER holds life and death in its proverbial hands.