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Published online
doi:10.1083/jcb.200702115
The Journal of Cell Biology, Vol. 179, No. 3, 485-500
The Rockefeller University Press, 0021-9525 $30.00
© Filimonenko et al.
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Article

Functional multivesicular bodies are required for autophagic clearance of protein aggregates associated with neurodegenerative disease



Maria Filimonenko1, Susanne Stuffers1, Camilla Raiborg1, Ai Yamamoto2, Lene Malerød1, Elizabeth M.C. Fisher3, Adrian Isaacs4, Andreas Brech1, Harald Stenmark1, and Anne Simonsen1

1 Centre for Cancer Biomedicine, University of Oslo and Department of Biochemistry, The Norwegian Radium Hospital, Montebello, N-0310 Oslo, Norway
2 Department of Physiology and Cellular Biophysics, Columbia University, College of Physicians and Surgeons, New York, NY 10032
3 Department of Neurodegenerative Disease, 4 MRC Prion Unit, Institute of Neurology, University College London, London WC1N 3BG, England, UK

Correspondence to Anne Simonsen: Anne.Simonsen{at}rr-research.no

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.

S. Stuffers and C. Raiborg contributed equally to this paper.

Abbreviations used in this paper: Alfy, autophagy-linked FYVE protein; ALS, amyotrophic lateral sclerosis; Atg, autophagy defective; CHMP2B, charged multivesicular body protein 2B/chromatin-modifying protein 2B; dox, doxycycline; EEA1, early endosome antigen 1; ESCRT, endosomal sorting complex required for transport; FTD, frontotemporal dementia; FTLD-U, frontotemporal lobar degeneration with ubiquitin deposits; HD, Huntington's disease; Hrs, hepatocyte growth factor–regulated tyrosine kinase substrate; Htt, Huntingtin; ILV, intraluminal vesicles; LBPA, lyso-bisphosphatidic acid; LC3, light chain 3; MVB, multivesicular body; TDP-43, TAR DNA-binding protein 43; Tsg101, tumor susceptibility gene 101; Vps, vacuolar protein sorting.


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