Inhibition of tau aggregation in a novel Caenorhabditis elegans model of tauopathy mitigates proteotoxicity

被引:140
作者
Fatouros, Chronis [1 ,2 ,5 ,6 ]
Pir, Ghulam Jeelani [7 ,8 ]
Biernat, Jacek [7 ,8 ]
Koushika, Sandhya Padmanabhan [10 ]
Mandelkow, Eckhard [7 ,8 ,9 ]
Mandelkow, Eva-Maria [7 ,8 ,9 ]
Schmidt, Enrico [1 ,2 ,5 ]
Baumeister, Ralf [1 ,2 ,3 ,4 ,5 ]
机构
[1] Univ Freiburg, Fac Biol, Inst Biol 3, D-79104 Freiburg, Germany
[2] Univ Freiburg, Fac Med, Ctr Biochem & Mol Cell Res ZBMZ, D-79104 Freiburg, Germany
[3] Univ Freiburg, Ctr Biol Signalling Studies BIOSS, D-79104 Freiburg, Germany
[4] Univ Freiburg, Freiburg Ctr Adv Studies FRIAS, D-79104 Freiburg, Germany
[5] Ctr Biol Syst Anal ZBSA, D-79104 Freiburg, Germany
[6] Int Max Planck Res Sch Mol & Cell Biol IMPRS MCB, Freiburg, Germany
[7] German Ctr Neurodegenerat Dis DZNE, D-53175 Bonn, Germany
[8] Max Planck Inst Neurol Res MPINF, D-50931 Cologne, Germany
[9] CAESAR Res Ctr, D-53175 Bonn, Germany
[10] Tata Inst Fundamental Res, Dept Biol Sci, Bombay 400005, Maharashtra, India
关键词
MICROTUBULE-ASSOCIATED PROTEIN; INDUCIBLE MOUSE MODELS; AXONAL-TRANSPORT; ALZHEIMERS-DISEASE; C-ELEGANS; MEDIATED NEURODEGENERATION; DETERMINES AGGREGATION; INDUCED NEUROTOXICITY; NEURONAL TOXICITY; TRANSGENIC MICE;
D O I
10.1093/hmg/dds190
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
Increased Tau protein amyloidogenicity has been causatively implicated in several neurodegenerative diseases, collectively called tauopathies. In pathological conditions, Tau becomes hyperphosphorylated and forms intracellular aggregates. The deletion of K280, which is a mutation that commonly appears in patients with frontotemporal dementia with Parkinsonism linked to chromosome 17, enhances Tau aggregation propensity (pro-aggregation). In contrast, introduction of the I277P and I308P mutations prevents -sheet formation and subsequent aggregation (anti-aggregation). In this study, we created a tauopathy model by expressing pro- or anti-aggregant Tau species in the nervous system of Caenorhabditis elegans. Animals expressing the highly amyloidogenic Tau species showed accelerated Tau aggregation and pathology manifested by severely impaired motility and evident neuronal dysfunction. In addition, we observed that the axonal transport of mitochondria was perturbed in these animals. Control animals expressing the anti-aggregant combination had rather mild phenotype. We subsequently tested several Tau aggregation inhibitor compounds and observed a mitigation of Tau proteotoxicity. In particular, a novel compound that crosses the bloodbrain barrier of mammals proved effective in ameliorating the motility as well as delaying the accumulation of neuronal defects. Our study establishes a new C. elegans model of Tau aggregation-mediated toxicity and supports the emerging notion that inhibiting the nucleation of Tau aggregation can be neuroprotective.
引用
收藏
页码:3587 / 3603
页数:17
相关论文
共 90 条
[81]   Chaperone networks: Tipping the balance in protein folding diseases [J].
Voisine, Cindy ;
Pedersen, Jesper Sondergaard ;
Morimoto, Richard I. .
NEUROBIOLOGY OF DISEASE, 2010, 40 (01) :12-20
[82]   Mutations of tau protein in frontotemporal dementia promote aggregation of paired helical filaments by enhancing local β-structure [J].
von Bergen, M ;
Barghorn, S ;
Li, L ;
Marx, A ;
Biernat, J ;
Mandelkow, EM ;
Mandelkow, E .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2001, 276 (51) :48165-48174
[83]   Stepwise proteolysis liberates tau fragments that nucleate the Alzheimer-like aggregation of full-length tau in a neuronal cell model [J].
Wang, Y. P. ;
Biernat, J. ;
Pickhardt, M. ;
Mandelkow, E. ;
Mandelkow, E.-M. .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2007, 104 (24) :10252-10257
[84]   Tau fragmentation, aggregation and clearance: the dual role of lysosomal processing [J].
Wang, Yipeng ;
Martinez-Vicente, Marta ;
Krueger, Ulrike ;
Kaushik, Susmita ;
Wong, Esther ;
Mandelkow, Eva-Maria ;
Cuervo, Ana Maria ;
Mandelkow, Eckhard .
HUMAN MOLECULAR GENETICS, 2009, 18 (21) :4153-4170
[85]   Regulation of Response Properties and Operating Range of the AFD Thermosensory Neurons by cGMP Signaling [J].
Wasserman, Sara M. ;
Beverly, Matthew ;
Bell, Harold W. ;
Sengupta, Piali .
CURRENT BIOLOGY, 2011, 21 (05) :353-362
[86]   Defects in synaptic vesicle docking in unc-18 mutants [J].
Weimer, RM ;
Richmond, JE ;
Davis, WS ;
Hadwiger, G ;
Nonet, ML ;
Jorgensen, EM .
NATURE NEUROSCIENCE, 2003, 6 (10) :1023-1030
[87]   The role of MSUT-2 in tau neurotoxicity: a target for neuroprotection in tauopathy? [J].
Wheeler, Jeanna M. ;
Guthrie, Chris R. ;
Kraemer, Brian C. .
BIOCHEMICAL SOCIETY TRANSACTIONS, 2010, 38 :973-976
[88]   Selective inhibition of Alzheimer disease-like tau aggregation by phenothiazines [J].
Wischik, CM ;
Edwards, PC ;
Lai, RYK ;
Roth, M ;
Harrington, CR .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1996, 93 (20) :11213-11218
[89]  
Wood W B, 1988, Dev Biol (N Y 1985), V5, P57
[90]   Amyloid-β-induced pathological behaviors are suppressed by Ginkgo biloba extract EGb 761 and ginkgolides in transgenic Caenorhabditis elegans [J].
Wu, Yanjue ;
Wu, Zhixin ;
Butko, Peter ;
Christen, Yves ;
Lambert, Mary P. ;
Klein, William L. ;
Link, Christopher D. ;
Luo, Yuan .
JOURNAL OF NEUROSCIENCE, 2006, 26 (50) :13102-13113