共 52 条
Proteolytic cleavage of polyglutamine-expanded ataxin-3 is critical for aggregation and sequestration of non-expanded ataxin-3
被引:97
作者:

Haacke, A
论文数: 0 引用数: 0
h-index: 0
机构: Max Planck Inst Biochem, Dept Cellular Biochem, D-82152 Martinsried, Germany

Broadley, SA
论文数: 0 引用数: 0
h-index: 0
机构: Max Planck Inst Biochem, Dept Cellular Biochem, D-82152 Martinsried, Germany

Boteva, R
论文数: 0 引用数: 0
h-index: 0
机构: Max Planck Inst Biochem, Dept Cellular Biochem, D-82152 Martinsried, Germany

Tzvetkov, N
论文数: 0 引用数: 0
h-index: 0
机构: Max Planck Inst Biochem, Dept Cellular Biochem, D-82152 Martinsried, Germany

Hartl, FU
论文数: 0 引用数: 0
h-index: 0
机构: Max Planck Inst Biochem, Dept Cellular Biochem, D-82152 Martinsried, Germany

Breuer, P
论文数: 0 引用数: 0
h-index: 0
机构:
Max Planck Inst Biochem, Dept Cellular Biochem, D-82152 Martinsried, Germany Max Planck Inst Biochem, Dept Cellular Biochem, D-82152 Martinsried, Germany
机构:
[1] Max Planck Inst Biochem, Dept Cellular Biochem, D-82152 Martinsried, Germany
[2] Natl Ctr Radiobiol & Radiat Protect, Dept Radiobiol, Sofia 1756, Bulgaria
关键词:
D O I:
10.1093/hmg/ddi472
中图分类号:
Q5 [生物化学];
Q7 [分子生物学];
学科分类号:
071010 ;
081704 ;
摘要:
Spinocerebellar ataxia type 3 (SCA3), like other polyglutamine (polyQ) diseases, is characterized by the formation of intraneuronal inclusions, but the mechanism underlying their formation is poorly understood. Here, we tested the 'toxic fragment hypothesis', which predicts that proteolytic production of polyQ-containing fragments from the full-length disease protein initiates the aggregation process associated with inclusion formation and cellular dysfunction. We demonstrate that the removal of the N-terminus of polyQ-expanded ataxin-3 (AT3) is required for aggregation in vitro and in vivo. Consistently, proteolytic cleavage of full-length, pathogenic AT3 initiates the formation of sodium dodecylsulfate-resistant aggregates in neuroblastoma cells. Although full-length AT3 does not readily aggregate on its own, it is susceptible to co-aggregation with polyQ-expanded AT3 fragments. Interestingly, interaction with soluble polyQ-elongated fragments causes a structural distortion of wild-type AT3 prior to the formation of stable co-aggregates. These results establish the critical role of C-terminal, proteolytic fragments of AT3 in the molecular pathomechanism of SCA3, in strong support of the toxic fragment hypothesis.
引用
收藏
页码:555 / 568
页数:14
相关论文
共 52 条
- [1] Structural modeling of ataxin-3 reveals distant homology to adaptins[J]. PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS, 2003, 50 (02) : 355 - 370Albrecht, M论文数: 0 引用数: 0 h-index: 0机构: Schloss Birlinghoven, Fraunhofer Inst Algorithms & Sci Comp, SCAI, D-53754 St Augustin, Germany Schloss Birlinghoven, Fraunhofer Inst Algorithms & Sci Comp, SCAI, D-53754 St Augustin, GermanyHoffmann, D论文数: 0 引用数: 0 h-index: 0机构: Schloss Birlinghoven, Fraunhofer Inst Algorithms & Sci Comp, SCAI, D-53754 St Augustin, GermanyEvert, BO论文数: 0 引用数: 0 h-index: 0机构: Schloss Birlinghoven, Fraunhofer Inst Algorithms & Sci Comp, SCAI, D-53754 St Augustin, GermanySchmitt, I论文数: 0 引用数: 0 h-index: 0机构: Schloss Birlinghoven, Fraunhofer Inst Algorithms & Sci Comp, SCAI, D-53754 St Augustin, GermanyWüllner, U论文数: 0 引用数: 0 h-index: 0机构: Schloss Birlinghoven, Fraunhofer Inst Algorithms & Sci Comp, SCAI, D-53754 St Augustin, GermanyLengauer, T论文数: 0 引用数: 0 h-index: 0机构: Schloss Birlinghoven, Fraunhofer Inst Algorithms & Sci Comp, SCAI, D-53754 St Augustin, Germany
- [2] A method for isolation and purification of specific antibodies to a protein fused to the GST[J]. ANALYTICAL BIOCHEMISTRY, 1996, 241 (01) : 140 - 142BarPeled, M论文数: 0 引用数: 0 h-index: 0机构: MICHIGAN STATE UNIV,US DOE,PLANT RES LAB,E LANSING,MI 48824 MICHIGAN STATE UNIV,US DOE,PLANT RES LAB,E LANSING,MI 48824Raikhel, NV论文数: 0 引用数: 0 h-index: 0机构: MICHIGAN STATE UNIV,US DOE,PLANT RES LAB,E LANSING,MI 48824 MICHIGAN STATE UNIV,US DOE,PLANT RES LAB,E LANSING,MI 48824
- [3] Roles of molecular chaperones in protein misfolding diseases[J]. SEMINARS IN CELL & DEVELOPMENTAL BIOLOGY, 2004, 15 (01) : 17 - 29Barral, JM论文数: 0 引用数: 0 h-index: 0机构: Max Planck Inst Biochem, Dept Cellular Biochem, D-82152 Martinsried, Germany Max Planck Inst Biochem, Dept Cellular Biochem, D-82152 Martinsried, GermanyBroadley, SA论文数: 0 引用数: 0 h-index: 0机构: Max Planck Inst Biochem, Dept Cellular Biochem, D-82152 Martinsried, Germany Max Planck Inst Biochem, Dept Cellular Biochem, D-82152 Martinsried, GermanySchaffar, G论文数: 0 引用数: 0 h-index: 0机构: Max Planck Inst Biochem, Dept Cellular Biochem, D-82152 Martinsried, Germany Max Planck Inst Biochem, Dept Cellular Biochem, D-82152 Martinsried, GermanyHartl, FU论文数: 0 引用数: 0 h-index: 0机构: Max Planck Inst Biochem, Dept Cellular Biochem, D-82152 Martinsried, Germany Max Planck Inst Biochem, Dept Cellular Biochem, D-82152 Martinsried, Germany
- [4] Caspase-mediated proteolysis of the polyglutamine disease protein ataxin-3[J]. JOURNAL OF NEUROCHEMISTRY, 2004, 89 (04) : 908 - 918Berke, SJS论文数: 0 引用数: 0 h-index: 0机构: Univ Iowa, Dept Neurol, Paulson Lab, Iowa City, IA 52242 USASchmied, FAF论文数: 0 引用数: 0 h-index: 0机构: Univ Iowa, Dept Neurol, Paulson Lab, Iowa City, IA 52242 USABrunt, ER论文数: 0 引用数: 0 h-index: 0机构: Univ Iowa, Dept Neurol, Paulson Lab, Iowa City, IA 52242 USAEllerby, LM论文数: 0 引用数: 0 h-index: 0机构: Univ Iowa, Dept Neurol, Paulson Lab, Iowa City, IA 52242 USAPaulson, HL论文数: 0 引用数: 0 h-index: 0机构: Univ Iowa, Dept Neurol, Paulson Lab, Iowa City, IA 52242 USA
- [5] The polyglutamine neurodegenerative protein ataxin-3 binds polyubiquitylated proteins and has ubiquitin protease activity[J]. HUMAN MOLECULAR GENETICS, 2003, 12 (23) : 3195 - 3205Burnett, B论文数: 0 引用数: 0 h-index: 0机构: Univ Penn, Sch Med, Dept Pharmacol, Philadelphia, PA 19104 USA Univ Penn, Sch Med, Dept Pharmacol, Philadelphia, PA 19104 USALi, FS论文数: 0 引用数: 0 h-index: 0机构: Univ Penn, Sch Med, Dept Pharmacol, Philadelphia, PA 19104 USA Univ Penn, Sch Med, Dept Pharmacol, Philadelphia, PA 19104 USAPittman, RN论文数: 0 引用数: 0 h-index: 0机构: Univ Penn, Sch Med, Dept Pharmacol, Philadelphia, PA 19104 USA Univ Penn, Sch Med, Dept Pharmacol, Philadelphia, PA 19104 USA
- [6] The polyglutamine neurodegenerative protein ataxin 3 regulates aggresome formation[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2005, 102 (12) : 4330 - 4335Burnett, BG论文数: 0 引用数: 0 h-index: 0机构: Univ Penn, Sch Med, Dept Pharmacol, Allentown, PA 18104 USA Univ Penn, Sch Med, Dept Pharmacol, Allentown, PA 18104 USAPittman, RN论文数: 0 引用数: 0 h-index: 0机构: Univ Penn, Sch Med, Dept Pharmacol, Allentown, PA 18104 USA Univ Penn, Sch Med, Dept Pharmacol, Allentown, PA 18104 USA
- [7] Mutant huntingtin promotes the fibrillogenesis of wild-type huntingtin - A potential mechanism for loss of huntingtin function in Huntington's disease[J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 2003, 278 (42) : 41452 - 41461Busch, A论文数: 0 引用数: 0 h-index: 0机构: Max Delbruck Ctr Mol Med, D-13125 Berlin, GermanyEngemann, S论文数: 0 引用数: 0 h-index: 0机构: Max Delbruck Ctr Mol Med, D-13125 Berlin, GermanyLurz, R论文数: 0 引用数: 0 h-index: 0机构: Max Delbruck Ctr Mol Med, D-13125 Berlin, GermanyOkazawa, H论文数: 0 引用数: 0 h-index: 0机构: Max Delbruck Ctr Mol Med, D-13125 Berlin, GermanyLehrach, H论文数: 0 引用数: 0 h-index: 0机构: Max Delbruck Ctr Mol Med, D-13125 Berlin, GermanyWanker, EE论文数: 0 引用数: 0 h-index: 0机构: Max Delbruck Ctr Mol Med, D-13125 Berlin, Germany
- [8] Huntington's disease age-of-onset linked to polyglutamine aggregation nucleation[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2002, 99 (18) : 11884 - 11889Chen, SM论文数: 0 引用数: 0 h-index: 0机构: Univ Tennessee, Med Ctr, Grad Sch Med, Knoxville, TN 37920 USAFerrone, FA论文数: 0 引用数: 0 h-index: 0机构: Univ Tennessee, Med Ctr, Grad Sch Med, Knoxville, TN 37920 USAWetzel, R论文数: 0 引用数: 0 h-index: 0机构: Univ Tennessee, Med Ctr, Grad Sch Med, Knoxville, TN 37920 USA
- [9] Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain[J]. SCIENCE, 1997, 277 (5334) : 1990 - 1993DiFiglia, M论文数: 0 引用数: 0 h-index: 0机构: UNIV LONDON UNIV COLL, DEPT ANAT & DEV BIOL, LONDON WC1E 6BT, ENGLANDSapp, E论文数: 0 引用数: 0 h-index: 0机构: UNIV LONDON UNIV COLL, DEPT ANAT & DEV BIOL, LONDON WC1E 6BT, ENGLANDChase, KO论文数: 0 引用数: 0 h-index: 0机构: UNIV LONDON UNIV COLL, DEPT ANAT & DEV BIOL, LONDON WC1E 6BT, ENGLANDDavies, SW论文数: 0 引用数: 0 h-index: 0机构: UNIV LONDON UNIV COLL, DEPT ANAT & DEV BIOL, LONDON WC1E 6BT, ENGLANDBates, GP论文数: 0 引用数: 0 h-index: 0机构: UNIV LONDON UNIV COLL, DEPT ANAT & DEV BIOL, LONDON WC1E 6BT, ENGLANDVonsattel, JP论文数: 0 引用数: 0 h-index: 0机构: UNIV LONDON UNIV COLL, DEPT ANAT & DEV BIOL, LONDON WC1E 6BT, ENGLANDAronin, N论文数: 0 引用数: 0 h-index: 0机构: UNIV LONDON UNIV COLL, DEPT ANAT & DEV BIOL, LONDON WC1E 6BT, ENGLAND
- [10] Ubiquitin-mediated sequestration of normal cellular proteins into polyglutamine aggregates[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2003, 100 (15) : 8892 - 8897Donaldson, KM论文数: 0 引用数: 0 h-index: 0机构: Novartis Res Fdn, Dept Canc & Cell Biol, Genom Inst, San Diego, CA 92121 USALi, W论文数: 0 引用数: 0 h-index: 0机构: Novartis Res Fdn, Dept Canc & Cell Biol, Genom Inst, San Diego, CA 92121 USAChing, KA论文数: 0 引用数: 0 h-index: 0机构: Novartis Res Fdn, Dept Canc & Cell Biol, Genom Inst, San Diego, CA 92121 USABatalov, S论文数: 0 引用数: 0 h-index: 0机构: Novartis Res Fdn, Dept Canc & Cell Biol, Genom Inst, San Diego, CA 92121 USATsai, CC论文数: 0 引用数: 0 h-index: 0机构: Novartis Res Fdn, Dept Canc & Cell Biol, Genom Inst, San Diego, CA 92121 USAJoazeiro, CAP论文数: 0 引用数: 0 h-index: 0机构: Novartis Res Fdn, Dept Canc & Cell Biol, Genom Inst, San Diego, CA 92121 USA