DnaJA1 Antagonizes Constitutive Hsp70-Mediated Stabilization of Tau

被引:47
作者
Abisambra, Jose F. [1 ]
Jinwal, Umesh K. [2 ]
Suntharalingam, Amirthaa [1 ]
Arulselvam, Karthik [1 ]
Brady, Sarah [1 ]
Cockman, Matthew [1 ]
Jin, Ying [1 ]
Zhang, Bo [1 ]
Dickey, Chad A. [1 ]
机构
[1] Univ S Florida, Byrd Alzheimers Res Inst, Dept Mol Med, Tampa, FL 33613 USA
[2] Univ S Florida, Byrd Alzheimers Res Inst, Coll Pharm, Tampa, FL 33613 USA
基金
美国国家卫生研究院;
关键词
tau; chaperones; DnaJA1; Hsp70; Alzheimer's disease; MOLECULAR CHAPERONE; ALZHEIMERS-DISEASE; TRANSGENIC MICE; ATPASE ACTIVITY; HSP70; DOMAIN; CONSERVATION; MACHINES; PROTEINS; MUTATION;
D O I
10.1016/j.jmb.2012.02.003
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
Tau aggregation and amyloidogenesis are common hallmarks for neurodegenerative disorders called tauopathies. The molecular chaperone network constitutes the cellular defense against insults such as tau aggregation. However, chaperone effects on tau are dichotomous. Loss of taus microtubule-binding activity facilitates an inappropriate chaperone interaction that promotes an amyloidogenic tau conformation. Conversely, other chaperones are capable of promoting tau clearance. Here, we demonstrate that a critical contributor to tau triage is the DnaJ-binding domain of Hsp70 proteins. In particular, over-expression of the constitutive DnaJ, DnaJA1, mediated tau clearance, while knockdown facilitated tau accumulation. This clearance was not specific to distinct pathogenic tau species. The activity of DnaJA1 was attenuated by concomitant increases in Hsp70. Tau reductions facilitated by DnaJA1 were dependent on the integrity of lysines known to be poly-ubiquitinated in human Alzheimer's brain. In vivo, DnaJA1 and tau levels were inversely correlated. The effects of DnaJA1 were partially specific: DnaJA1 reduced the levels of a polyQ protein but had no significant effect on a-synuclein levels. These data suggest that DnaJA1 triages all tau species for ubiquitin-dependent clearance mechanisms. Moreover, the levels of DnaJA1 and Hsp70 seem to play against each other with regard to tau: as DnaJA1 levels increase, tau levels are reduced, but this can be prevented if Hsp70 levels are simultaneously induced. Thus, the DnaJ repertoire possibly represents a powerful set of genetic modifiers for tau pathogenesis. Further investigations could provide new insights about triage decisions that facilitate or prevent amyloidogenesis of tau and other proteins associated with neurodegenerative disease. (C) 2012 Elsevier Ltd. All rights reserved.
引用
收藏
页码:653 / 661
页数:9
相关论文
共 31 条
[1]   Phosphorylation Dynamics Regulate Hsp27-Mediated Rescue of Neuronal Plasticity Deficits in Tau Transgenic Mice [J].
Abisambra, Jose F. ;
Blair, Laura J. ;
Hill, Shannon E. ;
Jones, Jeffrey R. ;
Kraft, Clara ;
Rogers, Justin ;
Koren, John, III ;
Jinwal, Umesh K. ;
Lawson, Lisa ;
Johnson, Amelia G. ;
Wilcock, Donna ;
O'Leary, John C. ;
Jansen-West, Karen ;
Muschol, Martin ;
Golde, Todd E. ;
Weeber, Edwin J. ;
Banko, Jessica ;
Dickey, Chad A. .
JOURNAL OF NEUROSCIENCE, 2010, 30 (46) :15374-15382
[2]   LDLR Expression and Localization Are Altered in Mouse and Human Cell Culture Models of Alzheimer's Disease [J].
Abisambra, Jose F. ;
Fiorelli, Tina ;
Padmanabhan, Jaya ;
Neame, Peter ;
Wefes, Inge ;
Potter, Huntington .
PLOS ONE, 2010, 5 (01)
[3]   Cytoskeleton proteins are modulators of mutant tau-induced neurodegeneration in Drosophila [J].
Blard, Olivier ;
Feuillette, Sebastien ;
Bou, Jacqueline ;
Chaumette, Boris ;
Frebourg, Thierry ;
Campion, Dominique ;
Lecourtois, Magalie .
HUMAN MOLECULAR GENETICS, 2007, 16 (05) :555-566
[4]   hsp70 genes in the human genome:: Conservation and differentiation patterns predict a wide array of overlapping and specialized functions [J].
Brocchieri, Luciano ;
de Macario, Everly Conway ;
Macario, Alberto J. L. .
BMC EVOLUTIONARY BIOLOGY, 2008, 8 (1)
[5]   The Hsp70 and Hsp60 chaperone machines [J].
Bukau, B ;
Horwich, AL .
CELL, 1998, 92 (03) :351-366
[6]  
Cheetham ME, 1998, CELL STRESS CHAPERON, V3, P28, DOI 10.1379/1466-1268(1998)003<0028:SFAEOD>2.3.CO
[7]  
2
[8]   Redox-regulated cochaperone activity of the human DnaJ homolog Hdj2 [J].
Choi, HI ;
Lee, SP ;
Kim, KS ;
Hwang, CY ;
Lee, YR ;
Chae, SK ;
Kim, YS ;
Chae, HZ ;
Kwon, KS .
FREE RADICAL BIOLOGY AND MEDICINE, 2006, 40 (04) :651-659
[9]   The lumenal domain of Sec63p stimulates the ATPase activity of BiP and mediates BiP recruitment to the translocon in Saccharomyces cerevisiae [J].
Corsi, AK ;
Schekman, R .
JOURNAL OF CELL BIOLOGY, 1997, 137 (07) :1483-1493
[10]   Alzheimer disease-specific conformation of hyperphosphorylated paired helical filament-tau is polyubiquitinated through Lys-48, Lys-11, and Lys-6 ubiquitin conjugation [J].
Cripps, D ;
Thomas, SN ;
Jeng, Y ;
Yang, F ;
Davies, P ;
Yang, AJ .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2006, 281 (16) :10825-10838