The pathways leading from aberrant Prion protein (PrP) metabolism to neurodegeneration are poorly understood. Some familial PrP mutants generate increased CtmPrP, a transmembrane isoform associated with disease. In other disease situations, a potentially toxic cytosolic form (termed cyPrP) might be produced. However, the mechanisms by which CtmPrP or cyPrP cause selective neuronal dysfunction are unknown. Here, we show that both CtmPrP and cyPrP can interact with and disrupt the function of Mahogunin (Mgrn), a cytosolic ubiquitin ligase whose loss causes spongiform neurodegeneration. Cultured cells and transgenic mice expressing either CtmPrP-producing mutants or cyPrP partially phenocopy Mgrn depletion, displaying aberrant lysosomal morphology and loss of Mgrn in selected brain regions. These effects were rescued by either Mgrn overexpression, competition for PrP-binding sites, or prevention of cytosolic PrP exposure. Thus, transient or partial exposure of PrP to the cytosol leads to inappropriate Mgrn sequestration that contributes to neuronal dysfunction and disease.

Inactivation of mahogunin, an E3 ubiquitin ligase, causes a spongiform encephalopathy resembling prion disease. Chakrabarti and Hegde (2009) now report that prion proteins with aberrant topologies inactivate mahogunin, providing a plausible explanation for certain aspects of prion pathology.

In mad cow disease, misfolded proteins called prions punch holes in the brain, eventually destroying it. Inherited prion diseases, which are rare and passed through families, do the same thing. But it's long been a puzzle why prions attack neurons more than other types of cells, and how they do their damage. In a new study, researchers propose that prions deplete a poorly understood protein that normally keeps nerve cells healthy. The theory still has a ways to go before it's proven, but researchers are intrigued by this potential new twist on a mysterious disease. Prions are a faulty version of a healthy protein called PrP; when it misfolds, the results are disastrous. Yet researchers don't know exactly why. One argument suggests that whereas healthy PrP is normally located on the cell's surface, prions go astray and end up in the cytosol, the liquid found inside cells, somehow destroying them. The new study bolsters this theory. The first clues came in a paper published in 2003. In that work, researchers reported that mice lacking an obscure protein, Mahogunin, suffered a form of neurodegeneration much like prion disease. Cell biologists Ramanujan Hegde and Oishee Chakrabarti of the National Institute of Child Health and Human Development in Bethesda, Maryland, decided to probe deeper into the Mahogunin connection. The team tested whether artificial prion proteins, constructed to resemble real prions, interact with Mahogunin. They did--but because prions are sticky and adhere to almost anything, that wasn't enough proof. So the researchers showed that this interaction caused problems for Mahogunin in living cells: Adding the artificial prion depleted levels of Mahogunin, but when prions were stopped from entering the cytosol, Mahogunin levels remained normal. Finally, mice with a mutation in the PrP gene, which develop prion disease, also lost Mahogunin in some parts of their brains

Prion variants faithfully propagate across species barriers, but if the barrier is too high, new variants (mutants) are selected, as shown in a recent BMC Biology report. Protein sequence alteration can prevent accurate structural templating at filament ends producing prion variants.

Prions are proteins that convert between structurally and functionally distinct states, one or more of which is transmissible. In yeast, this ability allows them to act as non-Mendelian elements of phenotypic inheritance. To further our understanding of prion biology, we conducted a bioinformatic proteome-wide survey for prionogenic proteins in S. cerevisiae, followed by experimental investigations of 100 prion candidates. We found an unexpected amino acid bias in aggregation-prone candidates and discovered that 19 of these could also form prions. At least one of these prion proteins, Mot3, produces a bona fide prion in its natural context that increases population-level phenotypic heterogeneity. The self-perpetuating states of these proteins present a vast source of heritable phenotypic variation that increases the adaptability of yeast populations to diverse environments.

Prions, self-propagating protein structures that can be transmitted between cells and different organisms, usually consist of ordered protein aggregates. Alberti et al. (2009) now present a systematic approach for the discovery of new prions that expands the spectrum of their biological functions.

The infectious agents could aid yeast survival in harsh conditions ... Prions, the mis-folded proteins best known for causing diseases such as bovine spongiform encephalopathy in cows, scrapie in sheep and Creutzfeldt–Jakob disease in humans, could also help yeast survival, according to a study in the journal Cell1. "We think prions are really important," says co-author Simon Alberti of the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts. "When environmental conditions are harsh, they might allow a species to survive." The work, led by Susan Lindquist of the Whitehead Institute, bolsters the theory that prions might confer an evolutionary advantage, says Alberti. Lindquist first broached that idea nine years ago, after finding that a prion called PSI+ in the yeast Saccharomyces cerevisiae triggered heritable changes that could provide a way of adapting to fluctuating environments2. More recent work also suggests prions might play a role in memory in sea slugs and smell in mice. In the new work, a scan of the S. cerevisiae genome yielded 24 potential prion-forming proteins. Only five prions were known to exist in yeast before this study. The team focused on a protein called Mot3 and found that it can twist into a prion form. When in its normal shape, Mot3 suppresses yeast genes involved in building the cellular wall. But when Mot3 kinks into a prion, it loses this function and the wall-building genes activate. Hence, yeast carrying the Mot3 prions grew thicker, more robust cell walls. Under some conditions — such as low oxygen availability — a thicker wall will help yeast survive, says co-author Randal Halfmann, also at the Whitehead Institute.