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.