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Functional multivesicular bodies are required for autophagic clearance of protein aggregates associated with neurodegenerative disease
Open accessAbstract
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.
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“CHMP2B downregulation or expression of disease-associated CHMP2B mutants in Drosophila and mammalian cell lines results in aberrant endosomal structures, impaired autophagosome maturation, and cytosolic TARDBP aggregates [264,265,268,269].”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [268]
In the citing paper
“Further corroborating the central role of MVBs in the maintenance of neuronal proteostasis, MVBs are essential for the clearance of ubiquitinated TARDBP, which accumulates in ALS and frontotemporal lobar degeneration (Filimonenko et al, 2007).”
From Autophagy in major human diseases (2021) · cites this paper as Filimonenko et al, 2007
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LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing.
Kabeya, Y., Mizushima, N., Ueno, T., Yamamoto, A., Kirisako, T., Noda, T., Kominami, E., Ohsumi, Y., & Yoshimori, T. (2000) · The EMBO Journal · doi:10.1093/emboj/19.21.5720 · Cited by 6,605
Self-citationUbiquitinated TDP-43 in Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis
Neumann, M., Sampathu, D. M., Kwong, L. K., Truax, A. C., Micsenyi, M. C., Chou, T. T., Bruce, J., Schuck, T., Grossman, M., Clark, C. M., et al. (2006) · Science · doi:10.1126/science.1134108 · Cited by 6,576
Pankiv, S., Clausen, T. H., Lamark, T., Brech, A., Bruun, J.-A., Outzen, H., Øvervatn, A., Bjørkøy, G., & Johansen, T. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m702824200 · Cited by 4,578
Self-citationSuppression of basal autophagy in neural cells causes neurodegenerative disease in mice
Hara, T., Nakamura, K., Matsui, M., Yamamoto, A., Nakahara, Y., Suzuki-Migishima, R., Yokoyama, M., Mishima, K., Saito, I., Okano, H., et al. (2006) · Nature · doi:10.1038/nature04724 · Cited by 3,882
Self-citationAutophagy as a Regulated Pathway of Cellular Degradation
Klionsky, D. J., & Emr, S. D. (2000) · Science · doi:10.1126/science.290.5497.1717 · Cited by 3,630
Loss of autophagy in the central nervous system causes neurodegeneration in mice
Komatsu, M., Waguri, S., Chiba, T., Murata, S., Iwata, J.-I., Tanida, I., Ueno, T., Koike, M., Uchiyama, Y., Kominami, E., et al. (2006) · Nature · doi:10.1038/nature04723 · Cited by 3,500
Bjørkøy, G., Lamark, T., Brech, A., Outzen, H., Perander, M., Øvervatn, A., Stenmark, H., & Johansen, T. (2005) · The Journal of Cell Biology · doi:10.1083/jcb.200507002 · Cited by 3,276
Self-citationArai, T., Hasegawa, M., Akiyama, H., Ikeda, K., Nonaka, T., Mori, H., Mann, D., Tsuchiya, K., Yoshida, M., Hashizume, Y., et al. (2006) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2006.10.093 · Cited by 2,732
Ravikumar, B., Vacher, C., Berger, Z., Davies, J. E., Luo, S., Oroz, L. G., Scaravilli, F., Easton, D. F., Duden, R., O'Kane, C. J., et al. (2004) · Nature Genetics · doi:10.1038/ng1362 · Cited by 2,347
Impairment of the Ubiquitin-Proteasome System by Protein Aggregation
Bence, N., Sampat, R. M., & Kopito, R. R. (2001) · Science · doi:10.1126/science.292.5521.1552 · Cited by 2,209
LC3, GABARAP and GATE16 localize to autophagosomal membrane depending on form-II formation
Kabeya, Y., Mizushima, N., Yamamoto, A., Oshitani-Okamoto, S., Ohsumi, Y., & Yoshimori, T. (2004) · Journal of Cell Science · doi:10.1242/jcs.01131 · Cited by 1,394
Self-citationDissection of Autophagosome Formation Using Apg5-Deficient Mouse Embryonic Stem Cells
Mizushima, N., Yamamoto, A., Hatano, M., Kobayashi, Y., Kabeya, Y., Suzuki, K., Tokuhisa, T., Ohsumi, Y., & Yoshimori, T. (2001) · The Journal of Cell Biology · doi:10.1083/jcb.152.4.657 · Cited by 1,361
Self-citationA Unified Nomenclature for Yeast Autophagy-Related Genes
Klionsky, D. J., Cregg, J. M., Dunn, W. A., Emr, S. D., Sakai, Y., Sandoval, I. V., Sibirny, A. А., Subramani, S. E., Thumm, M., Marten Veenhuis, A., et al. (2003) · Developmental Cell · doi:10.1016/s1534-5807(03)00296-x · Cited by 1,305
Scherzinger, E., Lurz, R., Turmaine, M., Mangiarini, L., Hollenbach, B., Hasenbank, R., Bates, G. P., Davies, S. W., Lehrach, H., & Wanker, E. E. (1997) · Cell · doi:10.1016/s0092-8674(00)80514-0 · Cited by 1,291 · cited 3×
“Using differential detergent extraction, a technique often used as a quantitative measure of protein inclusion formation (Scherzinger et al., 1997; Wanker et al., 1999), we observed a shift in p62 from less stringent extraction buffers (1% Triton-X-100, soluble) into 2% SDS (insoluble) in…”
MethodThe prevalence of frontotemporal dementia
Ratnavalli, E., Brayne, C., Dawson, K. E., & Hodges, J. R. (2002) · Neurology · doi:10.1212/wnl.58.11.1615 · Cited by 1,182
EEA1 links PI(3)K function to Rab5 regulation of endosome fusion
Simonsen, A., Lippe, R., Christoforidis, S., Gaullier, J.-M., Brech, A., Callaghan, J., Toh, B.-H., Murphy, C., Zerial, M., & Stenmark, H. (1998) · Nature · doi:10.1038/28879 · Cited by 1,133
Self-citationReversal of Neuropathology and Motor Dysfunction in a Conditional Model of Huntington's Disease
Yamamoto, A., Lucas, J. J., & Hen, R. (2000) · Cell · doi:10.1016/s0092-8674(00)80623-6 · Cited by 1,068
Self-citationBabst, M., Katzmann, D. J., Estepa, E. J., Meerloo, T., & Emr, S. D. (2002) · Developmental Cell · doi:10.1016/s1534-5807(02)00220-4 · Cited by 865
Slot, J. W., Geuze, H. J., Gigengack, S., Lienhard, G. E., & James, D. E. (1991) · The Journal of Cell Biology · doi:10.1083/jcb.113.1.123 · Cited by 862
The Protein Network of HIV Budding
von Schwedler, U. K., Stuchell‐Brereton, M. D., Müller, B., Ward, D. M., Chung, H.-Y., Morita, E., Wang, H. E., Davis, T., He, G.-P., Cimbora, D. M., et al. (2003) · Cell · doi:10.1016/s0092-8674(03)00714-1 · Cited by 835
Mutations in the endosomal ESCRTIII-complex subunit CHMP2B in frontotemporal dementia
Skibinski, G., Parkinson, N. J., Brown, J. M., Chakrabarti, L., Lloyd, S. L., Hummerich, H., Nielsen, J. E., Hodges, J. R., Spillantini, M. G., Thusgaard, T., et al. (2005) · Nature Genetics · doi:10.1038/ng1609 · Cited by 822
Self-citationThe emerging shape of the ESCRT machinery
Williams, R. L., & Urbé, S. (2007) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2162 · Cited by 779
The prevalence and causes of dementia in people under the age of 65 years
Harvey, R. J. (2003) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp.74.9.1206 · Cited by 650
Neary, D., Snowden, J. S., & Mann, D. M. A. (2005) · The Lancet Neurology · doi:10.1016/s1474-4422(05)70223-4 · Cited by 558
Kuma, A., Matsui, M., & Mizushima, N. (2007) · Autophagy · doi:10.4161/auto.4012 · Cited by 555 · cited 2×
“As GFP-LC3 has the potential to associate with membranefree aggregates (Kuma et al., 2007), probably due to its complex formation with p62 (Bjorkoy et al.”
BackgroundTHE ESCRT COMPLEXES: Structure and Mechanism of a Membrane-Trafficking Network
Hurley, J. H., & Emr, S. D. (2006) · Annual Review of Biophysics and Biomolecular Structure · doi:10.1146/annurev.biophys.35.040405.102126 · Cited by 546
Vacuolar Import of Proteins and Organelles From The Cytoplasm
Klionsky, D. J., & Ohsumi, Y. (1999) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev.cellbio.15.1.1 · Cited by 466
Jana, N. R. (2001) · Human Molecular Genetics · doi:10.1093/hmg/10.10.1049 · Cited by 453
Snyder, H. M., Mensah, K., Theisler, C. M., Lee, J., Matouschek, A. T., & Wolozin, B. L. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m208641200 · Cited by 430
ALS phenotypes with mutations in CHMP2B (charged multivesicular body protein 2B)
Parkinson, N., Ince, P. G., Smith, M. O., Highley, R., Skibinski, G., Andersen, P. M., Morrison, K. E., Pall, H. S., Hardiman, O., Collinge, J., et al. (2006) · Neurology · doi:10.1212/01.wnl.0000231510.89311.8b · Cited by 395
Self-citationIsolation and Characterization of Rat Liver Amphisomes
Berg, T. O., Fengsrud, M., Strømhaug, P. E., Berg, T., & Seglen, P. O. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.34.21883 · Cited by 385
Bampton, E. T. W., Goemans, C. G., Niranjan, D., Mizushima, N., & Tolkovsky, A. M. (2005) · Autophagy · doi:10.4161/auto.1.1.1495 · Cited by 369
Autophagy-mediated clearance of huntingtin aggregates triggered by the insulin-signaling pathway
Yamamoto, A., Cremona, M. L., & Rothman, J. E. (2006) · The Journal of Cell Biology · doi:10.1083/jcb.200510065 · Cited by 361
Self-citationFYVE and coiled-coil domains determine the specific localisation of Hrs to early endosomes
Raiborg, C., Bremnes, B., Mehlum, A., Gillooly, D. J., D’Arrigo, A., Stang, E., & Stenmark, H. (2001) · Journal of Cell Science · doi:10.1242/jcs.114.12.2255 · Cited by 319
Self-citationIwata, A., Christianson, J. C., Bucci, M., Ellerby, L., Nukina, N., Forno, L. S., & Kopito, R. R. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0505801102 · Cited by 318
Lysosomal killing of Mycobacterium mediated by ubiquitin-derived peptides is enhanced by autophagy
Alonso, S., Pethe, K., Russell, D. G., & Purdy, G. E. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0700036104 · Cited by 318
Rieder, S., & Emr, S. D. (1997) · Molecular Biology of the Cell · doi:10.1091/mbc.8.11.2307 · Cited by 305
Vadlamudi, R. K., Joung, I., Strominger, J. L., & Shin, J. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.34.20235 · Cited by 299
Simonsen, A., Birkeland, H. C. G., Gillooly, D. J., Mizushima, N., Kuma, A., Yoshimori, T., Slagsvold, T., Brech, A., & Stenmark, H. (2004) · Journal of Cell Science · doi:10.1242/jcs.01287 · Cited by 293
Self-citationSTAM and Hrs Are Subunits of a Multivalent Ubiquitin-binding Complex on Early Endosomes
Bache, K. G., Raiborg, C., Mehlum, A., & Stenmark, H. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m210843200 · Cited by 286
Self-citationPrelysosomal convergence of autophagic and endocytic pathways
Gordon, P. B., & Seglen, P. O. (1988) · Biochemical and Biophysical Research Communications · doi:10.1016/0006-291x(88)90556-6 · Cited by 281 · cited 2×
“compartments containing both autophagic and endocytic material (Gordon and Seglen, 1988).”
BackgroundUrushitani, M., Kurisu, J., Tsukita, K., & Takahashi, R. (2002) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2002.01211.x · Cited by 278
The Autophagic and Endocytic Pathways Converge at the Nascent Autophagic Vacuoles
Liou, W., Geuze, H. J., Geelen, M. J. H., & Slot, J. W. (1997) · The Journal of Cell Biology · doi:10.1083/jcb.136.1.61 · Cited by 276
Bishop, N. E., Horman, A., & Woodman, P. G. (2002) · The Journal of Cell Biology · doi:10.1083/jcb.200112080 · Cited by 266
Endosomal and non-endosomal functions of ESCRT proteins
Slagsvold, T., Pattni, K., Malerød, L., & Stenmark, H. (2006) · Trends in Cell Biology · doi:10.1016/j.tcb.2006.04.004 · Cited by 238
Self-citation[24] Membrane filter assay for detection of amyloid-like polyglutamine-containing protein aggregates
Wanker, E. E., Scherzinger, E., Heiser, V., Sittler, A., Eickhoff, H., & Lehrach, H. R. (1999) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/s0076-6879(99)09026-6 · Cited by 234
Endosome Sorting and Autophagy Are Essential for Differentiation and Virulence of Leishmania major
Besteiro, S., Williams, R., Morrison, L. S., Coombs, G. H., & Mottram, J. C. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m512307200 · Cited by 224
Tooze, J., Hollinshead, M. S., Ludwig, T. E., Howell, K. E., Hoflack, B., & Kern, H. (1990) · The Journal of Cell Biology · doi:10.1083/jcb.111.2.329 · Cited by 207
Martı́n-Aparicio, E., Yamamoto, A., Hernández, F., Hen, R., Ávila, J., & Lucas, J. J. (2001) · Journal of Neuroscience · doi:10.1523/jneurosci.21-22-08772.2001 · Cited by 172
Self-citationBache, K. G., Stuffers, S., Malerød, L., Slagsvold, T., Raiborg, C., Lechardeur, D., Wälchli, S., Lukács, G. L., Brech, A., & Stenmark, H. (2006) · Molecular Biology of the Cell · doi:10.1091/mbc.e05-10-0915 · Cited by 166
Self-citationSKD1 AAA ATPase-Dependent Endosomal Transport is Involved in Autolysosome Formation.
Nara, A., Mizushima, N., Yamamoto, A., Kabeya, Y., Ohsumi, Y., & Yoshimori, T. (2002) · Cell Structure and Function · doi:10.1247/csf.27.29 · Cited by 144
Self-citationA Reassessment of the Neuropathology of Frontotemporal Dementia Linked to Chromosome 3
Holm, I. E., Englund, E. M., Mackenzie, I. R., Johannsen, P., & Isaacs, A. M. (2007) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/nen.0b013e3181567f02 · Cited by 141
Self-citationAlix regulates cortical actin and the spatial distribution of endosomes
Cabezas, A., Bache, K. G., Brech, A., & Stenmark, H. (2005) · Journal of Cell Science · doi:10.1242/jcs.02382 · Cited by 122
Self-citationTalbot, K., & Ansorge, O. (2006) · Human Molecular Genetics · doi:10.1093/hmg/ddl202 · Cited by 90
Role of autophagy in the clearance of mutant huntingtin: A step towards therapy?
Ravikumar, B., & Rubinsztein, D. C. (2006) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2006.08.008 · Cited by 78
A dual function for Deep orange in programmed autophagy in the Drosophila melanogaster fat body
Lindmo, K., Simonsen, A., Brech, A., Finley, K. D., Rusten, T. E., & Stenmark, H. (2006) · Experimental Cell Research · doi:10.1016/j.yexcr.2006.03.002 · Cited by 78
Self-citationRoudier, N., Lefebvre, C., & Legouis, R. (2005) · Traffic · doi:10.1111/j.1600-0854.2005.00309.x · Cited by 76
Can autophagy protect against neurodegeneration caused by aggregate-prone proteins?
Ravikumar, B., & Rubinsztein, D. C. (2004) · Neuroreport · doi:10.1097/00001756-200411150-00001 · Cited by 64
Mutational Analysis of Csc1/Vps4p: Involvement of Endosome in Regulation of Autophagy in Yeast.
Shirahama, K., Noda, T., & Ohsumi, Y. (1997) · Cell Structure and Function · doi:10.1247/csf.22.501 · Cited by 62
CHMP2B mutations are not a common cause of frontotemporal lobar degeneration
Cannon, A. D., Baker, M., Boeve, B. F., Josephs, K. A., Knopman, D. S., Petersen, R. C., Parisi, J. E., Dickison, D., Adamson, J. L., Snowden, J. S., et al. (2006) · Neuroscience Letters · doi:10.1016/j.neulet.2005.12.056 · Cited by 62
Autophagic vacuoles fuse with the prelysosomal compartment in cultured rat fibroblasts.
Punnonen, E., Autio, S., Kaija, H., & Reunanen, H. (1993) · PubMed · Cited by 48
Rizzu, P., van Mil, S. E., Anar, B., Rosso, S. M., Kaat, L. D., Heutink, P., & Swieten, J. C. V. (2006) · American Journal of Medical Genetics Part B Neuropsychiatric Genetics · doi:10.1002/ajmg.b.30410 · Cited by 37
Flagged first, then by citations
Research works printed but not linked: 3
- 1993, Eur. J. Cell Biol., 61, 54
- 2006, Am. J. Med. Genet. B. Neuropsychiatr. Genet., 141, 944
- 2007, Nat. Rev. Mol. Cell Biol., 8, 355
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Self-citation
Metadata
- Authors
- Filimonenko, M., Stuffers, S., Raiborg, C., Yamamoto, A., Malerød, L., Fisher, E. M. C., Isaacs, A., Brech, A., Stenmark, H., & Simonsen, A.
- Affiliations
- University of Oslo (NO)
- Columbia University (US)
- University College London (GB)
- MRC Prion Unit (GB)
- Corresponding author
- Simonsen, Anne
- ORCID
- Venue
- The Journal of Cell Biology
- Publisher
- Rockefeller University Press
- Published
- 2007-11-05
- Volume
- 179
- Issue
- 3
- Pages
- 485-500
- ISSN
- 0021-9525 (ISSN-L)
- 1540-8140
- PMC
- PMC2064794
- OpenAlex
- W2103275390
- Cited by
- 626
- References
- 62
- Citations by year
- 2026: 13 · 2025: 26 · 2024: 20 · 2023: 15 · 2022: 18 · 2021: 35 · 2020: 29 · 2019: 27 · 2018: 41 · 2017: 31 · 2016: 46 · 2015: 34 · 2014: 43 · 2013: 36 · 2012: 40
- FWCI
- 29.80
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Cell Biology (publishedVersion)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Health Sciences › Medicine › Clinical Neurology › Amyotrophic Lateral Sclerosis Research
- Keywords
- multivesicular bodies, ESCRT, CHMP2B, autophagy, protein aggregates, neurodegenerative diseases, TDP-43, polyglutamine aggregates, Huntington's disease, amyotrophic lateral sclerosis, frontotemporal dementia, p62, ESCRT-III
- MeSH terms
- Autophagy, Cell Membrane, HeLa Cells, Humans, Huntington Disease, Models, Biological, Mutation, Nerve Tissue Proteins, Neurons, Phenotype, Protein Binding, Endosomes, Neurodegenerative Diseases, Ubiquitin, Endosomal Sorting Complexes Required for Transport
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