Nine neurodegenerative diseases are caused by expanded polyglutamine (polyQ) tracts in different proteins, such as huntingtin in Huntington's disease and ataxin 3 in spinocerebellar ataxia type 3 (SCA3)1,2. Age at onset of disease decreases with increasing polyglutamine length in these proteins and the normal length also varies3. PolyQ expansions drive pathogenesis in these diseases, as isolated polyQ tracts are toxic, and an N-terminal huntingtin fragment comprising exon 1, which occurs in vivo as a result of alternative splicing4, causes toxicity. Although such mutant proteins are prone to aggregation5, toxicity is also associated with soluble forms of the proteins6. The function of the polyQ tracts in many normal cytoplasmic proteins is unclear. One such protein is the deubiquitinating enzyme ataxin 3 (refs 7, 8), which is widely expressed in the brain9,10. Here we show that the polyQ domain enables wild-type ataxin 3 to interact with beclin 1, a key initiator of autophagy11. This interaction allows the deubiquitinase activity of ataxin 3 to protect beclin 1 from proteasome-mediated degradation and thereby enables autophagy. Starvation-induced autophagy, which is regulated by beclin 1, was particularly inhibited in ataxin-3-depleted human cell lines and mouse primary neurons, and in vivo in mice. This activity of ataxin 3 and its polyQ-mediated interaction with beclin 1 was competed for by other soluble proteins with polyQ tracts in a length-dependent fashion. This competition resulted in impairment of starvation-induced autophagy in cells expressing mutant huntingtin exon 1, and this impairment was recapitulated in the brains of a mouse model of Huntington's disease and in cells from patients. A similar phenomenon was also seen with other polyQ disease proteins, including mutant ataxin 3 itself. Our data thus describe a specific function for a wild-type polyQ tract that is abrogated by a competing longer polyQ mutation in a disease protein, and identify a deleterious function of such mutations distinct from their propensity to aggregate.

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Table of contents – Volume 545, Issue 7652

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Tables of content are generated automatically and are based on records of articles contained that are available in the TIB-Portal index. Due to missing records of articles, the volume display may be incomplete, even though the whole journal is available at TIB.

Trump's empty chairs rob science of a voice in government
| 2017
5
Empty-chair syndrome
| 2017
5
Integrity and PIs
| 2017
Integrity starts with the health of research groups
| 2017
6
What pause?
| 2017
Increased scrutiny of climate-change models should be welcomed
| 2017
7
No researcher is too junior to fix science
Tregoning, John | 2017
Arctic drilling, controversial reforms and new views of Saturn
| 2017
10
SEVEN DAYS: The news in brief
| 2017
13
Researchers frustrated by Italian misconduct probe
Abbott, Alison | 2017
14
Dreams of the Stone Age dated in southern Africa breakthrough
Sarah Wild | 2017
14
Dreams of the Stone Age dated for first time in southern Africa
Wild, Sarah | 2017
Europe's billion-euro quantum project takes shape
Gibney, Elizabeth | 2017
16
Billion-euro quantum project takes shape
Elizabeth Gibney | 2017
Party drug's power to fight depression puzzles scientists?
Reardon, Sara | 2017
17
Party drug puzzles scientists
Sara Reardon | 2017
BioRxiv preprint server gets cash boost from Chan Zuckerberg Initiative
Callaway, Ewen | 2017
18
CORRECTION
| 2017
18
BioRxiv bankrolled
Ewen Callaway | 2017
The shock tactics set to shake up immunology
Fox, Douglas | 2017
20
The electric cure
Douglas Fox | 2017
23
Antibiotic resistance has a language problem
Mendelson, Marc / Balasegaram, Manica / Jinks, Tim / Pulcini, Celine / Sharland, Mike | 2017
26
Palaeontology: Evolution with teeth
Humphrey, L. | 2017
27
Books in brief
Kiser, B. | 2017
28
Medical Research: Pitching the big tent of modern microbiology
Jermy, Andrew | 2017
30
Nomenclature: Share names for dinosaur divisions
Holtz, Thomas R | 2017
30
Germany: Note limitations of DNA legislation.(Brief article)
Staubach, Fabian | 2017
30
Soil: Restore earthworms to rebuild topsoil
Blakemore, Robert / Hochkirch, Axel | 2017
30
Publishing: One submission to all journals
Birkhead, T. / Montgomerie, R. | 2017
30
Germany: Note limitations of DNA legislation
Staubach, F. | 2017
30
Correspondence
| 2017
30
Publishing: One submission to all journals.(Brief article)
Birkhead, Tim / Montgomerie, Robert | 2017
32
Archaeology: Of rats and resilience
Diamond, Jared | 2017
32
Of rats and resilience
Jared Diamond | 2017
33
Neurodegeneration: Role of repeats in protein clearance
Martin, Dale D. O / Hayden, Michael R | 2017
33
Role of repeats in protein clearance
Dale D O Martin / Michael R Hayden | 2017
35
Organic chemistry: Nickel steps towards selectivity
Gaunt, M. / Williamson, P. | 2017
35
Nickel steps towards selectivity
Matthew Gaunt / Patrick Williamson | 2017
36
Molecular genetics: Chaperone protein gets personal
Siegal, Mark L | 2017
36
Chaperone protein gets personal
Mark L Siegal | 2017
37
The 'pause' unpacked
James S Risbey / Stephan Lewandowsky | 2017
37
Climate science: The 'pause' unpacked
Risbey, James S / Lewandowsky, Stephan | 2017
39
50 & 100 Years Ago
| 2017
39
Human development: Advances in mini-brain technology
Camp, J. Gray / Treutlein, Barbara | 2017
39
50 Years Ago/100 Years Ago
| 2017
39
Advances in mini-brain technology
J Gray Camp / Barbara Treutlein | 2017
41
Reconciling controversies about the global warming hiatus
Medhaug, Iselin / Stolpe, Martin B / Fischer, Erich M / Knutti, Reto | 2017
48
Cell diversity and network dynamics in photosensitive human brain organoids
Quadrato, Giorgia / Nguyen, Tuan / Macosko, Evan Z / Sherwood, John L / Min Yang, Sung / Berger, Daniel R / Maria, Natalie / Scholvin, Jorg / Goldman, Melissa / Kinney, Justin P et al. | 2017
54
Assembly of functionally integrated human forebrain spheroids
Birey, Fikri / Andersen, Jimena / Makinson, Christopher D / Islam, Saiful / Wei, Wu / Huber, Nina / Fan, H. Christina / Metzler, Kimberly R. Cordes / Panagiotakos, Georgia / Thom, Nicholas et al. | 2017
60
T-cell invigoration to tumour burden ratio associated with anti-PD-1 response
Huang, Alexander C / Postow, Michael A / Orlowski, Robert J / Mick, Rosemarie / Bengsch, Bertram / Manne, Sasikanth / Xu, Wei / Harmon, Shannon / Giles, Josephine R / Wenz, Brandon et al. | 2017
66
Visualizing multistep elevator-like transitions of a nucleoside transporter
Hirschi, Marscha / Johnson, Zachary Lee / Lee, Seok-Yong | 2017
71
Observation of the frozen charge of a Kondo resonance
Desjardins, M. M / Viennot, J. J / Dartiailh, M. C / Bruhat, L. E / Delbecq, M. R / Lee, M / Choi, M.-S / Cottet, A / Kontos, T | 2017
75
Observed quantization of anyonic heat flow
Banerjee, Mitali / Heiblum, Moty / Rosenblatt, Amir / Oreg, Yuval / Feldman, Dima E / Stern, Ady / Umansky, Vladimir | 2017
80
Dual-phase nanostructuring as a route to high-strength magnesium alloys
Wu, Ge / Chan, Ka-Cheung / Zhu, Linli / Sun, Ligang / Lu, Jian | 2017
84
Remote carboxylation of halogenated aliphatic hydrocarbons with carbon dioxide
Juli-Hernndez, Francisco / Moragas, Toni / Cornella, Josep / Martin, Ruben | 2017
89
Burgess Shale fossils illustrate the origin of the mandibulate body plan
Aria, Cdric / Caron, Jean-Bernard | 2017
93
The mitochondrial Na+/Ca^sup 2+^ exchanger is essential for Ca^sup 2+^ homeostasis and viability
Timothy S Luongo / Jonathan P Lambert / Polina Gross / Mary Nwokedi / Alyssa A Lombardi / Santhanam Shanmughapriya / April C Carpenter / Devin Kolmetzky / Erhe Gao / Jop H van Berlo et al. | 2017
93
The mitochondrial Na+/Ca2+ exchanger is essential for Ca2+ homeostasis and viability
Luongo, Timothy S / Lambert, Jonathan P / Gross, Polina / Nwokedi, Mary / Lombardi, Alyssa A / Shanmughapriya, Santhanam / Carpenter, April C / Kolmetzky, Devin / Gao, Erhe / van Berlo, Jop H et al. | 2017
98
Tumour ischaemia by interferon-γ resembles physiological blood vessel regression
Thomas Kammertoens / Christian Friese / Ainhoa Arina / Christian Idel / Dana Briesemeister / Michael Rothe / Andranik Ivanov / Anna Szymborska / Giannino Patone / Severine Kunz et al. | 2017
103
Transmission of cytokinesis forces via E-cadherin dilution and actomyosin flows
Pinheiro, Diana / Hannezo, Edouard / Herszterg, Sophie / Bosveld, Floris / Gaugue, Isabelle / Balakireva, Maria / Wang, Zhimin / Cristo, Ins / Rigaud, Stphane U / Markova, Olga et al. | 2017
108
Polyglutamine tracts regulate beclin 1-dependent autophagy
Ashkenazi, Avraham / Bento, Carla F / Ricketts, Thomas / Vicinanza, Mariella / Siddiqi, Farah / Pavel, Mariana / Squitieri, Ferdinando / Hardenberg, Maarten C / Imarisio, Sara / Menzies, Fiona M et al. | 2017
112
Structural insight into allosteric modulation of protease-activated receptor 2
Cheng, Robert K. Y / Fiez-Vandal, Cdric / Schlenker, Oliver / Edman, Karl / Aggeler, Birte / Brown, Dean G / Brown, Giles A / Cooke, Robert M / Dumelin, Christoph E / Dor, Andrew S et al. | 2017
116
Corrigendum: Elucidation of the biosynthesis of the methane catalyst coenzyme F430
Moore, Simon J / Sowa, Sven T / Schuchardt, Christopher / Deery, Evelyne / Lawrence, Andrew D / Ramos, Jos Vazquez / Billig, Susan / Birkemeyer, Claudia / Chivers, Peter T / Howard, Mark J et al. | 2017
116
Corrigendum: Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota.(Correction notice)
Forslund, Kristoffer / Hildebrand, Falk / Nielsen, Trine / Falony, Gwen / Le Chatelier, Emmanuelle / Sunagawa, Shinichi / Prifti, Edi / Vieira-Silva, Sara / Gudmundsdottir, Valborg / Pedersen, Helle Krogh et al. | 2017
116
Corrigendum: Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota
Forslund, K. / Hildebrand, F. / Nielsen, T. / Falony, G. / Le Chatelier, E. / Sunagawa, S. / Prifti, E. / Vieira-Silva, S. / Gudmundsdottir, V. / Pedersen, H. K. | 2017
116
Erratum: Effective combinatorial immunotherapy for castration-resistant prostate cancer
Lu, Xin / Horner, James W / Paul, Erin / Shang, Xiaoying / Troncoso, Patricia / Deng, Pingna / Jiang, Shan / Chang, Qing / Spring, Denise J / Sharma, Padmanee et al. | 2017
116
ERRATUM
| 2017
116
CORRIGENDUM
| 2017
117
Disks back from the dead
Baker, Monya | 2017
119
Pocket laboratories
Perkel, Jeffrey M | 2017
128
A trip to Central Park
Robson, Michael Adam | 2017

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