CHIP and Hsp70 regulate tau ubiquitination, degradation and aggregation

Molecular chaperones, ubiquitin ligases and proteasome impairment have been implicated in several neurodegenerative diseases, including Alzheimer's and Parkinson's disease, which are characterized by accumulation of abnormal protein aggregates (e.g. tau and alpha-synuclein respectively). Here we report that CHIP, an ubiquitin ligase that interacts directly with Hsp70/90, induces ubiquitination of the microtubule associated protein, tau. CHIP also increases tau aggregation. Consistent with this observation, diverse of tau lesions in human postmortem tissue were found to be immunopositive for CHIP. Conversely, induction of Hsp70 through treatment with either geldanamycin or heat shock factor 1 leads to a decrease in tau steady-state levels and a selective reduction in detergent insoluble tau. Furthermore, 30-month-old mice overexpressing inducible Hsp70 show a significant reduction in tau levels. Together these data demonstrate that the Hsp70/CHIP chaperone system plays an important role in the regulation of tau turnover and the selective elimination of abnormal tau species. Hsp70/CHIP may therefore play an important role in the pathogenesis of tauopathies and also represents a potential therapeutic target.

[1]  R. A. Crowther,et al.  Multiple isoforms of human microtubule-associated protein tau: sequences and localization in neurofibrillary tangles of Alzheimer's disease , 1989, Neuron.

[2]  P. Auluck,et al.  Pharmacological prevention of Parkinson disease in Drosophila , 2002, Nature Medicine.

[3]  C. Duyckaerts,et al.  Cortical tangles in progressive supranuclear palsy. , 1994, Journal of neural transmission. Supplementum.

[4]  Akihiko Takashima,et al.  Chaperones increase association of tau protein with microtubules , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[5]  E. Mandelkow,et al.  Overexpression of Tau Protein Inhibits Kinesin-dependent Trafficking of Vesicles, Mitochondria, and Endoplasmic Reticulum: Implications for Alzheimer's Disease , 1998, The Journal of cell biology.

[6]  R. Neve,et al.  Identification of cDNA clones for the human microtubule-associated protein tau and chromosomal localization of the genes for tau and microtubule-associated protein 2. , 1986, Brain research.

[7]  John Q. Trojanowski,et al.  Chaperone Suppression of α-Synuclein Toxicity in a Drosophila Model for Parkinson's Disease , 2001, Science.

[8]  P. Connell,et al.  Identification of CHIP, a Novel Tetratricopeptide Repeat-Containing Protein That Interacts with Heat Shock Proteins and Negatively Regulates Chaperone Functions , 1999, Molecular and Cellular Biology.

[9]  D. Cyr,et al.  The Hsc70 co-chaperone CHIP targets immature CFTR for proteasomal degradation , 2000, Nature Cell Biology.

[10]  K. Kosik,et al.  Structure and novel exons of the human tau gene. , 1992, Biochemistry.

[11]  K. Titani,et al.  Fetal‐Type Phosphorylation of the τ in Paired Helical Filaments , 1992 .

[12]  A Klug,et al.  Mutation in the tau gene in familial multiple system tauopathy with presenile dementia. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[13]  P. Connell,et al.  The co-chaperone CHIP regulates protein triage decisions mediated by heat-shock proteins , 2000, Nature Cell Biology.

[14]  T. Hashikawa,et al.  CHIP is associated with Parkin, a gene responsible for familial Parkinson's disease, and enhances its ubiquitin ligase activity. , 2002, Molecular cell.

[15]  R. Crowther,et al.  Cloning and sequencing of the cDNA encoding an isoform of microtubule‐associated protein tau containing four tandem repeats: differential expression of tau protein mRNAs in human brain. , 1989, The EMBO journal.

[16]  P. Mcgeer,et al.  Appearance of paired nucleated, Tau-positive glia in patients with progressive supranuclear palsy brain tissue , 1992, Neuroscience Letters.

[17]  Michael A. Mancini,et al.  Chaperone suppression of aggregation and altered subcellular proteasome localization imply protein misfolding in SCA1 , 1998, Nature Genetics.

[18]  D. Cyr,et al.  CHIP Is a U-box-dependent E3 Ubiquitin Ligase , 2001, The Journal of Biological Chemistry.

[19]  J. Marx.  Cell biology. Ubiquitin lives up to its name. , 2002, Science.

[20]  L. Neckers,et al.  Inhibition of heat shock protein HSP90-pp60v-src heteroprotein complex formation by benzoquinone ansamycins: essential role for stress proteins in oncogenic transformation. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[21]  D. Yellon,et al.  Overexpression of the rat inducible 70-kD heat stress protein in a transgenic mouse increases the resistance of the heart to ischemic injury. , 1995, The Journal of clinical investigation.

[22]  J. Walker,et al.  Cloning and sequencing of the cDNA encoding a core protein of the paired helical filament of Alzheimer disease: identification as the microtubule-associated protein tau. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[23]  S. Minoshima,et al.  Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism , 1998, Nature.

[24]  C. Patterson,et al.  C-terminal Hsp-interacting protein slows androgen receptor synthesis and reduces its rate of degradation. , 2003, Archives of biochemistry and biophysics.

[25]  N. Vilaboa,et al.  Modulation of tolerance by mutant heat shock transcription factors. , 1999, Cell stress & chaperones.

[26]  N. Hirokawa.  Microtubule organization and dynamics dependent on microtubule-associated proteins. , 1994, Current opinion in cell biology.

[27]  K. Titani,et al.  Fetal-type phosphorylation of the tau in paired helical filaments. , 1992, Journal of neurochemistry.

[28]  J. Marx.  Ubiquitin Lives Up to Its Name , 2002, Science.

[29]  Y. Imai,et al.  Parkin Suppresses Unfolded Protein Stress-induced Cell Death through Its E3 Ubiquitin-protein Ligase Activity* , 2000, The Journal of Biological Chemistry.

[30]  S. Love,et al.  Alz-50, Ubiquitin and Tau Immunoreactivity of Neurofibrillary Tangles, Pick Bodies and Lewy Bodies , 1988, Journal of neuropathology and experimental neurology.

[31]  V. Godfrey,et al.  CHIP activates HSF1 and confers protection against apoptosis and cellular stress , 2003, The EMBO journal.

[32]  J. Trojanowski,et al.  Chaperone suppression of alpha-synuclein toxicity in a Drosophila model for Parkinson's disease. , 2002, Science.

[33]  K. Oyanagi,et al.  Corticobasal degeneration: etiopathological significance of the cytoskeletal alterations , 2004, Acta Neuropathologica.

[34]  Steven P. Gygi,et al.  CHIP-Hsc70 Complex Ubiquitinates Phosphorylated Tau and Enhances Cell Survival* , 2004, Journal of Biological Chemistry.

[35]  Isao Nishimura,et al.  Parkin Suppresses Dopaminergic Neuron-Selective Neurotoxicity Induced by Pael-R in Drosophila , 2003, Neuron.

[36]  G. Schellenberg,et al.  Tau is a candidate gene for chromosome 17 frontotemporal dementia , 1998, Annals of neurology.

[37]  H. Ksiȩżak-Reding,et al.  Ubiquitin immunoreactivity of paired helical filaments differs in Alzheimer’s disease and corticobasal degeneration , 1998, Acta Neuropathologica.

[38]  R. Voellmy,et al.  Repression of Heat Shock Transcription Factor HSF1 Activation by HSP90 (HSP90 Complex) that Forms a Stress-Sensitive Complex with HSF1 , 1998, Cell.

[39]  Ronald C. Petersen,et al.  Association of missense and 5′-splice-site mutations in tau with the inherited dementia FTDP-17 , 1998, Nature.

[40]  Jada Lewis.  Neurofibrillary tangles, amyotrophy and progressive motor disturbance in mice expressing mutant (P301L) tau protein , 2000, Nature Genetics.

[41]  J. Frydman,et al.  Molecular chaperones and the art of recognizing a lost cause , 2001, Nature Cell Biology.