Levels of the Mahogunin Ring Finger 1 E3 Ubiquitin Ligase Do Not Influence Prion Disease

Derek Silvius,George A Carlson,Abby Oehler,Stephen J Dearmond,Delisha Meishery,Rose Pitstick,Teresa M Gunn,Misol Ahn,Gregory S Barsh,Hyoung-Gon Lee

doi:10.1371/journal.pone.0055575

Abstract

Prion diseases are rare but invariably fatal neurodegenerative disorders. They are associated with spongiform encephalopathy, a histopathology characterized by the presence of large, membrane-bound vacuolar structures in the neuropil of the brain. While the primary cause is recognized as conversion of the normal form of prion protein (PrPC) to a conformationally distinct, pathogenic form (PrPSc), the cellular pathways and mechanisms that lead to spongiform change, neuronal dysfunction and death are not known. Mice lacking the Mahogunin Ring Finger 1 (MGRN1) E3 ubiquitin ligase develop spongiform encephalopathy by 9 months of age but do not become ill. In cell culture, PrP aberrantly present in the cytosol was reported to interact with and sequester MGRN1. This caused endo-lysosomal trafficking defects similar to those observed when Mgrn1 expression is knocked down, implicating disrupted MGRN1-dependent trafficking in the pathogenesis of prion disease. As these defects were rescued by over-expression of MGRN1, we investigated whether reduced or elevated Mgrn1 expression influences the onset, progression or pathology of disease in mice inoculated with PrPSc. No differences were observed, indicating that disruption of MGRN1-dependent pathways does not play a significant role in the pathogenesis of transmissible spongiform encephalopathy.

Highlights

Transmissible spongiform encephalopathies, are rare but invariably fatal neurodegenerative disorders that affect humans and animals [1,2]
Since Mgrn1 over-expression rescued the endo-lysosomal trafficking defects associated with the presence of cytosolically exposed forms of PrP in vitro [9], we set out to test whether Mgrn1 levels influence PrPSc-mediated prion disease in vivo by inoculating mice that express no Mgrn1 and mice that over-express Mgrn1 with Rocky Mountain Laboratory (RML) prions
To test whether loss of Mahogunin Ring Finger 1 (MGRN1) function can contribute to the pathogenesis of prion disease, male and female mice homozygous for the Mgrn1md2nc null mutation and heterozygous controls were inoculated with RML prions and carefully monitored for signs of illness and neurological symptoms associated with prion infection

Summary

Introduction

Transmissible spongiform encephalopathies, are rare but invariably fatal neurodegenerative disorders that affect humans and animals [1,2]. They are associated with misfolding and aggregation of the cellular prion protein, PrPC, into a proteaseresistant, pathogenic conformer referred to as PrPSc, with Sc referring to the prototypical Scrapie prion disease of sheep. Most prion diseases are characterized by spongiform changes, starting with the development of vacuoles in the neuropil and progressing to widespread vacuolation of the central nervous system (CNS). Despite progress in understanding the primary cause of prion diseases, the cellular and molecular mechanisms that lead to neurodegeneration and death are still under investigation

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