Tag Archives: Prions

What are prions for?

Prions existed in yeast billions of years before humanity came on the scene. Why are they still there? What are they for?  Immediately we are back in the Aristotelian world of teleology, where everything had a reason for existence and a purpose.  http://www.sparknotes.com/philosophy/aristotle/themes.html.  Teleology is simply impossible to avoid in biology. “Nothing in Biology Makes Sense Except in the Light of Evolution” is a famous quote from the magnificently named Theodosius Dobzhansky, which clothes naked teleology with respectable scientific garments.

Here’s an example of this sort of thing from back in the day.  When I was back in the Denver VA as a neurology resident dealing with the complications of immunosuppressants in Starzl’s early work on transplantation, we wondered what on earth the transplantation antigens were for.  All we knew then, is that they were important in transplant rejection. Surely they were not there to prevent cells of the same or another species from finding a new home in us.  Only later did we figure out that they were involved in antigen presentation.

A fascinating article from the first Science of the new year — http://science.sciencemag.org/content/359/6371/eaao5654 describes how the yeast organism might be using one of them (Sup35) — e.g. what the prion domains are for.  Normally the Sup35 protein functions to terminate messenger RNA (mRNA) translation into protein. However the first 123 amino acids of Sup35 can aggregate forming amyloid fibrils.  It contains a series of 9 amino acid repeats with consensus sequence PQGGYQQYN (single letter amino acid code — http://130.88.97.239/bioactivity/aacodefrm.html) which is similar to the human prion protein repeats (PHGGGWGQ).

This work showed that under a variety of stesses (energy depletion, lowering of intracellular pH) Sup35 doesn’t form amyloid-like prions, but something rather different — liquidlike spherical condensates, which subsequently solidify to form a protein gel.  Next to the prion domain is a very acidic region, important in formation of the condensate.  Low pH is seen in energy depletion, and protonates the acidic amino acids in the acidic region leading to condensate formation.   A mutated Sup35 containing only the prion domain and the acidic region will form the condensates as well in a pH dependent manner.  The condensates are far from irreversible (like prions) as they quickly disappear when the pH is raised.

If you take out the prion domain from Sup35, the catalytic region (a GTPase) in the carboxy terminal part forms irreversible aggregates — so the prion domain is in some way preventing this.

So basically the two other parts of Sup35 function to protect the business end of Sup35 from being totally put out of commission by irreversible aggregation.

The authors found that yeast cells containing Sup35 lacking the prion domain, after recovering from stress, showed impaired translational activity and a growth defect presumably because there was less functional Sup35 around. This may be what the prion domain is doing.

My guess is that the aggregation of Sup35 into actual prions has a function in yeast that we just haven’t figured out yet.

It will be interesting to see if other yeast prions (there are many) show the similar behavior (condensate formation under stress).

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A possible new player

Drug development is very hard because we don’t know all the players inside the cell. A recent paper describes an entirely new class of player — circular DNA derived from an ancient virus.  The authoress is Laura Manuelidis, who would have been a med school classmate had I chosen to go to Yale med instead of Penn.   She is the last scientist standing who doesn’t believe Prusiner’s prion hypothesis.  She didn’t marry the boss’s daughter being female, so she married the boss instead;  Elias Manuelidis a Yale neuropathologist who would be 99 today had he not passed away at 72 in 1992.

The circular DNAs go by the name of SPHINX  an acronym  for  Slow Progressive Hidden INfections of X origin.  They have no sequences in common with bacterial or eukaryotic DNA, but there some homology to a virus infecting Acinebacter, a wound pathogen common in soil and water.

How did she find them?  By doggedly pursuing the idea the neurodegenerative diseases such as Cruetzfeldt Jakob Disease (CJD) and scrapie were due to an infectious agent triggering aggregation of the prion protein.

As she says:  “The cytoplasm of CJD and scrapie-infected cells, but not control cells, also contains virus-like particle arrays and because we were able to isolate these nuclease-protected particles with quantitative recovery of infectivity, but with little or no detectable PrP (Prion Protein), we began to analyze protected nucleic acids. Using Φ29 rolling circle amplification, several circular DNA sequences of <5 kb (kilobases) with ORFs (Open Reading Frames) were thereby discovered in brain and cultured neuronal cell lines. These circular DNA sequences were named SPHINX elements for their initial association with slow progressive hidden infections of X origin."

SPHINX itself codes for a 324 amino acid protein, which is found in human brain, concentrated in synaptic boutons.  Strangely, even though the DNAs are presumably viral derived, they contain intervening sequences which don't code for protein.

The use of rolling circle amplification is quite clever, as it will copy only circular DNA.

Stanley Prusiner is sure to weigh in.  Remarkably, Prusiner was at Penn Med when I was and was even in my med school fraternity (Nu Sigma Nu)  primarily a place to eat lunch and dinner.  I probably ate with him, but have no recollection of him whatsoever.

Circular DNAs outside chromosomes are called plasmids. Bacteria are full of them. The best known eukaryote containing plasmids is yeast. Perhaps we have them as well. Manuelidis may be the first person to look.