title: Functional multivesicular bodies are required for autophagic clearance of protein aggregates associated with neurodegenerative disease.
abstract: The endosomal sorting complexes required for transport (ESCRTs) are required to sort integral membrane proteins into intralumenal vesicles of the multivesicular body (MVB). Mutations in the ESCRT-III subunit CHMP2B were recently associated with frontotemporal dementia and amyotrophic lateral sclerosis (ALS), neurodegenerative diseases characterized by abnormal ubiquitin-positive protein deposits in affected neurons. We show here that autophagic degradation is inhibited in cells depleted of ESCRT subunits and in cells expressing CHMP2B mutants, leading to accumulation of protein aggregates containing ubiquitinated proteins, p62 and Alfy. Moreover, we find that functional MVBs are required for clearance of TDP-43 (identified as the major ubiquitinated protein in ALS and frontotemporal lobar degeneration with ubiquitin deposits), and of expanded polyglutamine aggregates associated with Huntington's disease. Together, our data indicate that efficient autophagic degradation requires functional MVBs and provide a possible explanation to the observed neurodegenerative phenotype seen in patients with CHMP2B mutations.
authors.affiliation: Centre for Cancer Biomedicine, University of Oslo and Department of Biochemistry, The Norwegian Radium Hospital, Montebello, N-0310 Oslo, Norway.
authors.forename: Maria
authors.initials: M
authors.lastname: Filimonenko
authors.forename: Susanne
authors.initials: S
authors.lastname: Stuffers
authors.forename: Camilla
authors.initials: C
authors.lastname: Raiborg
authors.forename: Ai
authors.initials: A
authors.lastname: Yamamoto
authors.forename: Lene
authors.initials: L
authors.lastname: Malerød
authors.forename: Elizabeth M C
authors.initials: EM
authors.lastname: Fisher
authors.forename: Adrian
authors.initials: A
authors.lastname: Isaacs
authors.forename: Andreas
authors.initials: A
authors.lastname: Brech
authors.forename: Harald
authors.initials: H
authors.lastname: Stenmark
authors.forename: Anne
authors.initials: A
authors.lastname: Simonsen
mesh_terms: D001343:Autophagy; D002462:Cell Membrane / Q000378:metabolism; D056827:Endosomal Sorting Complexes Required for Transport; D011992:Endosomes / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D006816:Huntington Disease / Q000378:metabolism; D008954:Models, Biological; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000378:metabolism / Q000473:pathology*; D009474:Neurons / Q000378:metabolism; D010641:Phenotype; D011485:Protein Binding; D025801:Ubiquitin / Q000737:chemistry
chemical_list: C503812:CHMP2B protein, human; D056827:Endosomal Sorting Complexes Required for Transport; D009419:Nerve Tissue Proteins; D025801:Ubiquitin