The prion concept began with the recognition that certain proteins could act as templates to cause molecules of the same protein to fold into the same conformation, which could go on to template the folding of yet more protein. The first such proteins identified, called prion proteins (PrP), caused neurodegenerative diseases of humans and ungulates (including sheep and cows), and were transmissible to some extent within species, and to a much lesser extent between species.
Since then, the concept has been extended to include many of the proteins associated with neurodegenerative diseases, including amyloid-beta in Alzheimer’s disease, alpha-synuclein in Parkinson’s disease, and tau in the tauopathies. While there is little evidence to date suggesting that these proteins are spread between organisms, the strong similarities in templating and spreading between cells has led many in the field to use the term “prion” to describe them as well.
“From a cell biology standpoint, it is exactly like a prion,” Dr. Diamond said. A characteristic of PrP is the existence of strains, unique conformations that are passed on in the templating process.
While templating and cell-to-cell transmission have been previously shown for tau, faithful maintenance of strains has not, Dr. Diamond said. That led him to determine whether tau shared this characteristic with the PrPs. This is important, he said, because to the extent that prion mechanisms underlie the tauopathies, “only stably propagating strains can account for stereotyped clinical presentation” and spread through networks of brain neurons.
To test for the presence of strains in tau, Dr. Diamond used the aggregation-prone core of the protein, the repeat domain, bearing an aggregation-prone mutation, to transduce cells in culture. After several days, individual aggregate-containing cells were isolated and grown up separately. At the end of a month, Dr. Diamond analyzed the progeny cells to determine whether they contained identifiably different strains.
Based on aggregate morphology, he identified 20 different clones. Each clone maintained its inclusion type over the course of six months of cell culture, and thus, Dr. Diamond concluded, were true strains of tau aggregates.
Different strains induced different pathologies in mice expressing a mutant tau protein, and after two rounds of isolation and reinjection into naïve mice, the same strain as originally injected could be isolated again from the mouse brain. Within the brain, the tau aggregates spread from the site of injection to distant, synaptically connected regions.
Finally, Dr. Diamond searched for tau strains in the brains of 29 patients with tauopathies, including Alzheimer’s disease, corticobasal degeneration, progressive supranuclear palsy, and others. He isolated tau aggregates from each brain, and used them to induce inclusions in cell culture, and then classified the inclusions based on morphology, similar to the earlier identification of the 20 clones.
Four of the six AD brains induced a single type of inclusion; the two remaining AD brains induced predominantly that same type, and small amounts of a second type. Several patients with corticobasal degeneration contained the same two strains as the mixed-type AD patients, but in opposite proportions. Other diseases were more heterogeneous, with multiple types of inclusions both within a single patient and between patients with the same diagnosis.
“We are moving toward understanding these diverse neurodegenerative diseases based on the structure of the pathogenic forms of the protein,” Dr. Diamond said. “By the time we are done, I hope we will be able to diagnose diseases based on molecular structure, and use that to make predictions of clinical course and potentially even response to therapy.”
Read more about this research and its implications for understanding and treating neurodegenerative disease in the August 7 issue of Neurology Today. Browse our archives on prions and neurodegenerative disease: http://bit.ly/NT-prions.