CoChat
Sign Up
PreprintCited by 3Genetic Neurodegenerative DiseasesAutophagy in Disease and TherapyLysosomal Storage Disorders Research

The DOI matches its Crossref record; 4 of the 4 references it cites were found in a registry or an index.

Autophagy preferentially degrades non-fibrillar polyQ aggregates

Open access
Zhao, Dorothy Y., Bäuerlein, Felix J.B., Saha, Itika, Hartl, F. Ulrich, Baumeister, Wolfgang, Wilfling, Florian·2023·bioRxiv (Cold Spring Harbor Laboratory)
DOI 10.1101/2023.08.08.552291

Preprint — published as 10.1016/j.molcel.2024.04.018

Open this paper in CoChat — free accountOpen PDF

Abstract

Summary: Aggregation of proteins containing expanded polyglutamine (polyQ) repeats is the cytopathologic hallmark of a group of dominantly inherited neurodegenerative diseases, including Huntington’s disease (HD). Huntingtin (Htt), the disease protein of HD, forms amyloid-like fibrils by liquid-to-solid phase transition. Macroautophagy has been proposed to clear polyQ aggregates, but the efficiency of aggrephagy is limited. Here, we used cryo-electron tomography to visualize the interactions of autophagosomes with polyQ aggregates in cultured cells in situ . We found that an amorphous aggregate phase exists next to the radially organized polyQ fibrils. Autophagosomes preferentially engulfed this amorphous material, mediated by interactions between the autophagy receptor p62/SQSTM1 and the non-fibrillar aggregate surface. In contrast, amyloid fibrils excluded p62 and evaded clearance, resulting in trapping of autophagic structures. These results suggest that the limited efficiency of autophagy in clearing polyQ aggregates is due to the inability of autophagosomes to interact productively with the non-deformable, fibrillar disease aggregates.

Overview

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1101/2023.08.08.552291

Cites

4 of 4 references verified0 citation errors · 0 not checkable

Statistics

Verification

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Citations

Cites

Flagged first, then by citations

Research works printed but not linked: 105

  1. 10.1038/s41586-020-2992-3 · DOI
  2. 2016, Site-Specific Cryo-focused Ion Beam Sample Preparation Guided by 3D Correlative Microscopy, Biophys J, 110, 860, 10.1016/j.bpj.2015.10.053 · DOI · Paper page
  3. 10.1016/j.expneurol.2011.12.013 · DOI
  4. 10.1038/nature02998 · DOI · Paper page
  5. 10.1038/nature22078 · DOI · Paper page
  6. 10.1016/j.tcb.2020.08.007 · DOI
  7. 10.1016/j.cell.2017.08.009 · DOI
  8. Bence, N.F. , Sampat, R.M. , and Kopito, R.R. (2001). Impairment of the ubiquitin-proteasome system by protein aggregation. Science. · DOI
  9. 10.1016/j.molcel.2004.12.021 · DOI
  10. 10.1038/s41467-020-18952-1 · DOI
  11. 2022, In situ structural analysis reveals membrane shape transitions during autophagosome formation, Proc Natl Acad Sci U S A, 119, e2209823119, 10.1073/pnas.2209823119 · DOI
  12. Boland, B. , Yu, W.H. , Corti, O. , Mollereau, B. , Henriques, A. , Bezard, E. , Pastores, G.M. , Rubinsztein, D.C. , Nixon, R.A. , Duchen, M.R. , et al. (2018). Promoting the clearance of neurotoxic proteins in neurodegenerative disorders of ageing. Nature Reviews Drug Discovery. · DOI
  13. 10.1016/bs.mcb.2019.05.001 · DOI
  14. 10.1073/pnas.1920323117 · DOI
  15. 10.1146/annurev-biochem-061516-045115 · DOI · Paper page
  16. 10.1074/mcp.M113.031591 · DOI · Paper page
  17. 2008, MaxQuant enables high peptide identification rates, individualized p, p.b.-range mass accuracies and proteome-wide protein quantification. Nat Biotechnol, 26, 1367
  18. 10.1016/j.tcb.2017.01.001 · DOI
  19. DiFiglia, M. , Sapp, E. , Chase, K.O. , Davies, S.W. , Bates, G.P. , Vonsattel, J.P. , and Aronin, N. (1997). Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain. Science. · DOI · Paper page
  20. Felix J.B. Bäuerlein , J.C.P.-P., Rubén Fernández-Busnadiego (2022). Cryo-electron tomography of native Drosophila tissues vitrified by plunge freezing. bioRxiv doi: https://doi.org/10.1101/2021.04.14.437159. · DOI
  21. 10.1016/j.bpj.2015.10.043 · DOI
  22. 10.1083/jcb.200711112 · DOI
  23. Goel, S. , Oliva, R. , Jeganathan, S. , Bader, V. , Krause, L.J. , Kriegler, S. , Stender, I.D. , Christine, C.W. , Nakamura, K. , Hoffmann, J.E. , et al. (2023). Linear ubiquitination induces NEMO phase separation to activate NF-kappaB signaling. Life Sci Alliance 6. · DOI
  24. 2020, Visualizing Molecular Architectures of Cellular Condensates: Hints of Complex Coacervation Scenarios, Dev Cell, 55, 97, 10.1016/j.devcel.2020.09.003 · DOI
  25. 10.7554/eLife.06980 · DOI
  26. 10.1016/0092-8674(93)90585-E · DOI · Paper page
  27. Gruber, A. , Hornburg, D. , Antonin, M. , Krahmer, N. , Collado, J. , Schaffer, M. , Zubaite, G. , Lüchtenborg, C. , Sachsenheimer, T. , Brügger, B. , et al. (2018). Molecular and structural architecture of polyQ aggregates in yeast. Proceedings of the National Academy of Sciences of the United States of America. · DOI
  28. 10.1016/j.cell.2017.12.030 · DOI
  29. 10.1016/j.tibs.2006.06.009 · DOI
  30. 10.1038/s41580-018-0033-y · DOI · Paper page
  31. Hara, T. , Nakamura, K. , Matsui, M. , Yamamoto, A. , Nakahara, Y. , Suzuki-Migishima, R. , Yokoyama, M. , Mishima, K. , Saito, I. , Okano, H. , et al. (2006). Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. In Nature. · DOI · Paper page
  32. 10.1038/s41580-019-0101-y · DOI · Paper page
  33. 10.1016/j.cell.2016.07.001 · DOI
  34. Holmberg, C.I. , Staniszewski, K.E. , Mensah, K.N. , Matouschek, A. , and Morimoto, R.I. (2004). Inefficient degradation of truncated polyglutamine proteins by the proteasome. EMBO Journal. · DOI
  35. 10.1073/pnas.1521933113 · DOI
  36. 10.1016/j.jsb.2011.12.003 · DOI
  37. 10.1038/nm.4474 · DOI · Paper page
  38. Iwata, A. , Christianson, J.C. , Bucci, M. , Ellerby, L.M. , Nukina, N. , Forno, L.S. , and Kopito, R.R. (2005). Increased susceptibility of cytoplasmic over nuclear polyglutamine aggregates to autophagic degradation. Proceedings of the National Academy of Sciences of the United States of America. · DOI
  39. 2020, Structural basis of p62/SQSTM1 helical filaments and their role in cellular cargo uptake, Nat Commun, 11, 440, 10.1038/s41467-020-14343-8 · DOI
  40. 10.1016/j.molcel.2016.09.037 · DOI
  41. Kato, M. , Han, T.W. , Xie, S. , Shi, K. , Du, X. , Wu, L.C. , Mirzaei, H. , Goldsmith, E.J. , Longgood, J. , Pei, J. , et al. (2012). Cell-free formation of RNA granules: low complexity sequence domains form dynamic fibers within hydrogels. In Cell (Elsevier Inc.), pp. 753–767. · DOI · Paper page
  42. Kim, J. , Kundu, M. , Viollet, B. , and Guan, K.L. (2011). AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. In Nature Cell Biology. · DOI · Paper page
  43. Kim, Y.E. , Hosp, F. , Frottin, F. , Ge, H. , Mann, M. , Hayer-Hartl, M. , and Hartl, F.U. (2016). Soluble Oligomers of PolyQ-Expanded Huntingtin Target a Multiplicity of Key Cellular Factors. Molecular Cell. · DOI
  44. 10.4161/auto.5.5.8566 · DOI
  45. 10.1016/j.molcel.2009.01.020 · DOI · Paper page
  46. 10.1016/j.molcel.2019.09.005 · DOI
  47. Komatsu, M. , Waguri, S. , Chiba, T. , Murata, S. , Iwata, J.I. , Tanida, I. , Ueno, T. , Koike, M. , Uchiyama, Y. , Kominami, E. , et al. (2006). Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature. · DOI · Paper page
  48. 10.1093/nar/gky508 · DOI
  49. 10.1006/jsbi.1996.0013 · DOI
  50. 10.1126/science.aag3048 · DOI · Paper page
  51. Leitman, J. , Ulrich Hartl, F. , and Lederkremer, G.Z. (2013). Soluble forms of polyQ-expanded huntingtin rather than large aggregates cause endoplasmic reticulum stress. Nature Communications. · DOI
  52. 10.1016/j.cell.2018.09.048 · DOI · Paper page
  53. 2023, In situ snapshots along a mammalian selective autophagy pathway, Proc Natl Acad Sci U S A, 120, e2221712120, 10.1073/pnas.2221712120 · DOI
  54. Li, Z. , Wang, C. , Wang, Z. , Zhu, C. , Li, J. , Sha, T. , Ma, L. , Gao, C. , Yang, Y. , Sun, Y. , et al. (2019). Allele-selective lowering of mutant HTT protein by HTT–LC3 linker compounds. In Nature (Nature Publishing Group), pp. 1-7. · DOI · Paper page
  55. Lu, K. , Den Brave, F. , and Jentsch, S. (2017). Receptor oligomerization guides pathway choice between proteasomal and autophagic degradation. In Nature Cell Biology. · DOI
  56. 10.1016/j.cell.2022.03.005 · DOI
  57. 10.1016/j.jsb.2014.02.015 · DOI
  58. 10.1016/j.jsb.2005.07.007 · DOI
  59. 2018, Chloroquine inhibits autophagic flux by decreasing autophagosome-lysosome fusion, Autophagy, 14, 1435, 10.1080/15548627.2018.1474314 · DOI · Paper page
  60. Miller, J. , Arrasate, M. , Brooks, E. , Libeu, C.P. , Legleiter, J. , Hatters, D. , Curtis, J. , Cheung, K. , Krishnan, P. , Mitra, S. , et al. (2011). Identifying polyglutamine protein species in situ that best predict neurodegeneration. Nature Chemical Biology. · DOI
  61. 10.1038/s41556-018-0092-5 · DOI · Paper page
  62. 10.1016/j.jsb.2004.10.006 · DOI
  63. Nikolas Furthmann , L.A., Verian Bader , Alina Blusch , Simran Goel , Ana Sánchez-Vicente , Laura J. Krause , Prerna Grover , Victoria A. Trinkaus , Eva M. van Well , Maximilian Jaugstetter , Kristina Tschulik , Rune Busk Damgaard , Carsten Saft ,, and Gisa Ellrichmann , R.G., Arend Koch , Benjamin Englert , Markus Glatzel , F. Ulrich Hartl , Ken Nakamura , Chadwick W. Christine , Eric J. Huang , Jörg Tatzelt and Konstanze F. Winklhofer * (2023). NEMO reshapes the protein aggregate interface and promotes aggrephagy by co-1 condensation with p62. bioRxiv June 06, 2023. · DOI
  64. 10.1016/j.tibs.2018.02.003 · DOI
  65. Nixon, R.A. (2013). The role of autophagy in neurodegenerative disease. Nature Medicine. · DOI · Paper page
  66. Nthiga, T.M. , Shrestha, B.K. , Bruun, J.A. , Larsen, K.B. , Lamark, T. , and Johansen, T. (2021). Regulation of Golgi turnover by CALCOCO1-mediated selective autophagy. J Cell Biol 220. · DOI
  67. 10.1074/jbc.M111.252577 · DOI
  68. 10.1016/j.cell.2013.06.003 · DOI
  69. 10.1073/pnas.91.12.5355 · DOI
  70. Peskett, T.R. , Rau, F. , O’Driscoll, J. , Patani, R. , Lowe, A.R. , and Saibil, H.R. (2018). A Liquid to Solid Phase Transition Underlying Pathological Huntingtin Exon1 Aggregation. Molecular Cell. · DOI
  71. Ravikumar, B. (2002). Aggregate-prone proteins with polyglutamine and polyalanine expansions are degraded by autophagy. Human Molecular Genetics. · DOI
  72. 10.1016/j.jsb.2011.08.012 · DOI
  73. 10.1038/nm1066 · DOI · Paper page
  74. 10.1016/j.cell.2011.07.030 · DOI · Paper page
  75. Rusmini, P. , Cortese, K. , Crippa, V. , Cristofani, R. , Cicardi, M.E. , Ferrari, V. , Vezzoli, G. , Tedesco, B. , Meroni, M. , Messi, E. , et al. (2019). Trehalose induces autophagy via lysosomal-mediated TFEB activation in models of motoneuron degeneration. Autophagy. · DOI · Paper page
  76. 2023, The AAA+ chaperone VCP disaggregates Tau fibrils and generates aggregate seeds in a cellular system, Nat Commun, 14, 560, 10.1038/s41467-023-36058-2 · DOI
  77. 10.15252/embr.201948902 · DOI
  78. Sánchez, I. , Mahlke, C. , and Yuan, J. (2003). Pivotal role of oligomerization in expanded polyglutamine neurodegenerative disorders. Nature. · DOI
  79. 10.1074/mcp.RA119.001486 · DOI
  80. Sarkar, S. , Davies, J.E. , Huang, Z. , Tunnacliffe, A. , and Rubinsztein, D.C. (2007). Trehalose, a novel mTOR-independent autophagy enhancer, accelerates the clearance of mutant huntingtin and α-synuclein. Journal of Biological Chemistry. · DOI · Paper page
  81. Schaffar, G. , Breuer, P. , Boteva, R. , Behrends, C. , Tzvetkov, N. , Strippel, N. , Sakahira, H. , Siegers, K. , Hayer-Hartl, M. , and Hartl, F.U. (2004). Cellular toxicity of polyglutamine expansion proteins: Mechanism of transcription factor deactivation. In Molecular Cell. · DOI
  82. 10.1016/S0092-8674(00)80514-0 · DOI · Paper page
  83. 10.1038/nmeth.2019 · DOI · Paper page
  84. 10.1016/J.JSB.2016.06.020 · DOI
  85. 10.1073/pnas.0503634102 · DOI
  86. Stamatakou, E. , Wróbel, L. , Hill, S.M. , Puri, C. , Son, S.M. , Fujimaki, M. , Zhu, Y. , Siddiqi, F. , Fernandez-Estevez, M. , Manni, M.M. , et al. (2020). Mendelian neurodegenerative disease genes involved in autophagy. In Cell Discovery. · DOI
  87. 10.1038/s41422-018-0017-7 · DOI
  88. Tanaka, M. , Machida, Y. , Niu, S. , Ikeda, T. , Jana, N.R. , Doi, H. , Kurosawa, M. , Nekooki, M. , and Nukina, N. (2004). Trehalose alleviates polyglutamine-mediated pathology in a mouse model of Huntington disease. Nature Medicine. · DOI
  89. 10.1126/science.1067122 · DOI · Paper page
  90. 10.1038/s41467-021-25572-w · DOI
  91. 10.1038/nrm2993 · DOI
  92. van Well, E.M. , Bader, V. , Patra, M. , Sanchez-Vicente, A. , Meschede, J. , Furthmann, N. , Schnack, C. , Blusch, A. , Longworth, J. , Petrasch-Parwez, E. , et al. (2019). A protein quality control pathway regulated by linear ubiquitination. EMBO J 38. · DOI
  93. 10.1016/S1097-2765(04)00151-0 · DOI
  94. 10.1093/hmg/11.22.2689 · DOI
  95. 10.1016/S0140-6736(07)60111-1 · DOI
  96. 1999, Caspase activation during apoptotic cell death induced by expanded polyglutamine in N2a cells, Neuroreport, 10, 2435, 10.1097/00001756-199908200-00001 · DOI
  97. 10.1016/j.devcel.2011.02.006 · DOI
  98. 10.1016/j.molcel.2020.10.030 · DOI
  99. 10.1016/j.tins.2008.07.004 · DOI
  100. 10.1126/science.aad2033 · DOI
  101. Wurzer, B. , Zaffagnini, G. , Fracchiolla, D. , Turco, E. , Abert, C. , Romanov, J. , and Martens, S. (2015). Oligomerization of p62 allows for selection of ubiquitinated cargo and isolation membrane during selective autophagy. In eLife. · DOI
  102. 10.1016/j.molcel.2019.12.026 · DOI
  103. Zaffagnini, G. , Savova, A. , Danieli, A. , Romanov, J. , Tremel, S. , Ebner, M. , Peterbauer, T. , Sztacho, M. , Trapannone, R. , Tarafder, A.K. , et al. (2018). p62 filaments capture and present ubiquitinated cargos for autophagy. EMBO J 37. · DOI
  104. Zhang, G. , Wang, Z. , Du, Z. , and Zhang, H. (2018). mTOR Regulates Phase Separation of PGL Granules to Modulate Their Autophagic Degradation. In Cell (Cell Press), pp. 1492-1506.e1422. · DOI
  105. 10.1038/nmeth.4193 · DOI

Metadata

Authors
Zhao, D. Y., Bäuerlein, F. J. B., Saha, I., Hartl, F. U., Baumeister, W., & Wilfling, F.
Affiliations
  • Max Planck Institute of Biochemistry (DE)
  • Universitätsmedizin Göttingen (DE)
  • Max Planck Institute of Biophysics (DE)
Corresponding author
  • Zhao, Dorothy Y.
  • Hartl, F. Ulrich
  • Baumeister, Wolfgang
  • Wilfling, Florian
ORCID
Venue
bioRxiv (Cold Spring Harbor Laboratory)
Publisher
openRxiv
Published
2023-08-09
DOI
10.1101/2023.08.08.552291
OpenAlex
W4385706842
Cited by
3
References
4
Citations by year
2024: 2 · 2023: 1
Type
posted content
Language
en
Open access
Licence
cc-by-nc-nd
Locations
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • UCL Discovery (University College London) (submittedVersion)
Funders
Michael J. Fox Foundation for Parkinson's Research (ASAP-000282)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
  • Health Sciences › Medicine › Genetics (clinical) › Lysosomal Storage Disorders Research
Keywords
autophagy, polyglutamine aggregates, Huntington's disease, huntingtin, amyloid fibrils, aggrephagy, autophagosomes, p62, cryo-electron tomography, neurodegeneration, protein aggregation

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review