A paper out a few weeks ago in Nucleic Acids Research offers the possibility of a new diagnostic tool for detecting the progression of prion disease before a patient becomes symptomatic.
Bellingham 2012 “Small RNA deep sequencing reveals a distinct miRNA signature released in exosomes from prion-infected neuronal cells”
Before I read this, I didn’t know what an exosome was. It turns out that just as endosomes are membrane-bound vesicles which bud off from the inside of a cell’s plasma membrane, tinier vesicles can bud off the inside of an endosome. Then later if the endosome fuses with the cell membrane to release its cargo extracellularly, those tiny vesicles are released too and are thenceforth known as “exosomes,” free to roam the extracellular environment and bloodstream. People think they might be involved in intercellular signaling, as they carry a variety of RNA and proteins. There have been a few other papers noting an association between miRNA profiles in blood serum and various diseases, suggesting you could use exosomes isolated from a patient’s blood as a diagnostic tool. The standard test for prion disease today is to obtain CSF via lumbar puncture and test for the presence of proteins such as 14-3-3. By comparison, sequencing of exosome miRNA would be a less invasive way of testing for prion disease and, much more importantly, might be able to offer signals of disease progression before symptoms emerge.
That said, this paper represents a pretty preliminary result down that path. The study used only one line of mouse hypothalamic neurons in culture and only one prion strain (M1000, derived from Fukuoka-1 which in turn comes originally from human GSS brains). Within that model, the authors found a distinct exosomal miRNA signature of prion-infected cells: a consistent set of several specific miRNAs were found at heightened expression levels in exosomes from prion-infected neurons, along with a couple of miRNAs which were downregulated. It remains to be seen if this result will be consistent across different prion strains, whether it will translate from mouse to human and from cell culture to organism, and whether these exosomes would be found in the human bloodstream. The authors point to similarities between their miRNA profile and that observed in human CJD brains as well as in mouse and primate models of prion disease (the profile “agrees to some extent”). Still, we’ll need to see some in vivo and human studies before we know how usable this signature is as a diagnostic tool. Luckily the authors state their intention to follow up on that:
Evaluation of our exosomal miRNA signature in circulating exosomes derived from clinical plasma samples from sporadic and variant forms of human prion disease and in animal models infected with different prion strains will be the subject of our further studies.