Let’s talk about proteins for a few minutes – nasty, unfriendly proteins, of the sort that will ball up and crash out of solution the first chance they get. Anyone working in a protein purification lab will have encountered plenty of these, and will be familiar with the various tricks available to keep things in solution and off the bottom of the tube. But what about when this starts happening in a living system?
That’s the situation, of course, in a number of diseases – Alzheimer’s, Parkinson’s, ALS, CJD and many more (here’s a list just for amyloid proteins alone). And while there’s some room for cause-and-effect arguing in some of these, in others it seems clear that the primary event is protein aggregation. It’s a constant problem, as those folks expressing and purifying proteins in the lab will tell you, and it’s a constant problem in the cell as well. The beta-sheet structure is a key protein folding motif, but it can get out of hand. When things get out of hand (as they do in this structure, blogged about here recently), beta-sheet regions can start slapping onto each other like a stack of two-sided Velco pads. (In fact, you’d have to figure that there’s been evolutionary pressure away from such sequences and other crash-out-in-a-heap motifs).
The most dramatic (and unnerving) of the protein aggregation diseases are those caused by prions, which are proteins that can catalyze infectious misfolding. Stanley Prusiner got what was (at the time) a fairly controversial Nobel prize for his work in this field, but time has vindicated him. And he and his co-workers have just identified a new prion disease (the first in many years). The rare condition known as multiple system atrophy now appears to be caused by a prion version of alpha-synuclein, the same protein involved in Parkinson’s. (Whether Parkinson’s itself is caused (or at least exacerbated) by prions remains an open question).
And coincidentally, there is a new paper in Nature that reports transmissible beta-amyloid pathology in humans. The authors were studying tissue from patients who had died from iatrogenic CJD, bought on by cadaver-derived growth hormone treatment. That mode of therapy came to a gravel-spraying halt in about 1985, when the dangers of prion transmission had become clear, but the latency time is so terrifyingly long and unpredictable that people are still manifesting with the disease. Histopathology showed the presence of amyloid deposits in the gray matter and blood vessels, not associated with the CJD protein deposits. These are not seen in other patients who have had growth hormone therapy from other sources, not seen in another cohort of patients with other prion conditions, and none of these eight patients had any of the known genetic predispositions to amyloid deposition. The hypothesis is that these represent a transmissable amyloid pathology, which has never until now been demonstrated in humans (the most direct experiments to do so being ruled out for obvious reasons!) Animal models have shown that it’s possible, though.
This immediately suggests several things that have to be looked into: for one thing, can other patients be at risk of having amyloid pathology transmitted to them by surgical or medical procedures? Prion proteins, worryingly, are known to adhere to metal surfaces and to be resistant to many standard methods of cleaning and sterilization. Another larger question is whether amyloid diseases (including Alzheimer’s) have an infectious component in the general population. This paper certainly doesn’t prove that they do, of course, and there’s a lot of epidemiology (blood transfusion data and more) to suggest that Alzheimer’s, at least, is not spread in this way. But it does put the idea back on the table, to some extent, and since there’s less information on the potential transmissibility of the less common amyloid diseases, this is something that’s going to have to be looked into as well.
So what does one do about a prion disease? At the moment, the standard medical treatment is. . .nothing, basically. One of the most disturbing features of something like CJD is that we have no weapons against it at all. A lot of work has gone into trying to find agents that will interrupt the protein-folding cascade, but it’s a tall order. Protein aggregation tends to be a thermodynamic tar pit, and keeping things from sliding off into it is not easy. A number of aminothiazole compounds have shown efficacy in animal models of prion diseases, though, but (just to make things trickier) drug-resistant prions have been shown to develop under these conditions as well. If you’re looking for a major unsolved therapeutic problem, look no further.