title: Oligodendroglial deletion of ESCRT-I component TSG101 causes spongiform encephalopathy.
abstract: BACKGROUND
  Vacuolation of the central nervous system (CNS) is observed in patients with transmissible spongiform encephalopathy, HIV-related encephalopathy and some inherited diseases, but the underlying cellular mechanisms remain poorly understood. Mice lacking the mahogunin ring finger-1 (MGRN1) E3 ubiquitin ligase develop progressive, widespread spongiform degeneration of the CNS. MGRN1 ubiquitinates and regulates tumour susceptibility gene 101 (TSG101), a central component of the endosomal trafficking machinery. As loss of MGRN1 is predicted to cause partial TSG101 loss-of-function, we hypothesised that CNS vacuolation in Mgrn1 null mice may be caused by the accumulation of multi-cisternal endosome-like 'class E' vacuolar protein sorting (vps) compartments similar to those observed in Tsg101-depleted cells in culture.
  
  
  RESULTS
  To test this hypothesis, Tsg101 was deleted from mature oligodendroglia in vivo. This resulted in severe spongiform encephalopathy, histopathologically similar to that observed in Mgrn1 null mutant mice but with a more rapid onset. Vacuoles in the brains of Tsg101-deleted and Mgrn1 mutant mice labelled with endosomal markers, consistent with an endosomal origin. Vacuoles in the brains of mice inoculated with Rocky Mountain Laboratory (RML) prions did not label with these markers, indicating a different origin, consistent with previously published studies that indicate RML prions have a primary effect on neurons and cause vacuolation in an MGRN1-independent manner. Oligodendroglial deletion of Rab7, which mediates late endosome-to-lysosome trafficking and autophagosome-lysosome fusion, did not cause spongiform change.
  
  
  CONCLUSIONS
  Our data suggest that the formation of multi-cisternal 'class E' vps endosomal structures in oligodendroglia leads to vacuolation.
  
  
  CONCLUSIONS
  This work provides the first evidence that disrupting multi-vesicular body formation in oligodendroglia can cause white matter vacuolation and demyelination. HIV is known to hijack the endosomal sorting machinery, suggesting that HIV infection of the CNS may also act through this pathway to cause encephalopathy.
authors.affiliation: McLaughlin Research Institute, Great Falls, MT, 59405, USA.
authors.forename: Will P
authors.initials: WP
authors.lastname: Walker
authors.affiliation: Department of Pathology, Institute for Neurodegenerative Diseases, University of California, San Francisco, CA, 94143, USA.
authors.forename: Abby
authors.initials: A
authors.lastname: Oehler
authors.affiliation: Department of Developmental and Cell Biology, University of California, Irvine, CA, 92697, USA.
authors.forename: Aimee L
authors.initials: AL
authors.lastname: Edinger
authors.affiliation: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
authors.forename: Kay-Uwe
authors.initials: KU
authors.lastname: Wagner
authors.affiliation: McLaughlin Research Institute, Great Falls, MT, 59405, USA. tmg@mri.montana.edu.
authors.forename: Teresa M
authors.initials: TM
authors.lastname: Gunn
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D004268:DNA-Binding Proteins / Q000235:genetics*; D056827:Endosomal Sorting Complexes Required for Transport / Q000235:genetics*; D017353:Gene Deletion; D051379:Mice; D018345:Mice, Knockout; D009836:Oligodendroglia / Q000378:metabolism / Q000473:pathology*; D017096:Prion Diseases / Q000235:genetics* / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics; D020691:rab GTP-Binding Proteins / Q000235:genetics; D000090802:rab7 GTP-Binding Proteins; D000099177:Tsg101 Protein
chemical_list: D004268:DNA-Binding Proteins; D056827:Endosomal Sorting Complexes Required for Transport; D014157:Transcription Factors; D044767:Ubiquitin-Protein Ligases; D020691:rab GTP-Binding Proteins; D000090802:rab7 GTP-Binding Proteins; D000099177:Tsg101 Protein; C000716465:rab7 GTP-binding proteins, mouse; C470689:Mgrn1 protein, mouse
keywords: Endosomal sorting complex required for transport; Mahogunin ring finger-1; Spongiform neurodegeneration; Transmissible spongiform encephalopathy; Tumour susceptibility gene 101