CoChat
Sign Up
Cited by 323Alzheimer's disease research and treatmentsGenomics, phytochemicals, and oxidative stressAutophagy in Disease and Therapy

Nrf2 reduces levels of phosphorylated tau protein by inducing autophagy adaptor protein NDP52

Open access
Jo, Chulman, Gundemir, Soner, Pritchard, Susanne, Jin, Youngnam N., Rahman, Irfan, Johnson, Gail V. W.·2014·Nature Communications
DOI 10.1038/ncomms4496PMC PMC3990284
Open this paper in CoChat — free accountOpen PDF

Abstract

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a pivotal transcription factor in the defence against oxidative stress. Here we provide evidence that activation of the Nrf2 pathway reduces the levels of phosphorylated tau by induction of an autophagy adaptor protein NDP52 (also known as CALCOCO2) in neurons. The expression of NDP52, which we show has three antioxidant response elements (AREs) in its promoter region, is strongly induced by Nrf2, and its overexpression facilitates clearance of phosphorylated tau in the presence of an autophagy stimulator. In Nrf2-knockout mice, phosphorylated and sarkosyl-insoluble tau accumulates in the brains concurrent with decreased levels of NDP52. Moreover, NDP52 associates with phosphorylated tau from brain cortical samples of Alzheimer disease cases, and the amount of phosphorylated tau in sarkosyl-insoluble fractions is inversely proportional to that of NDP52. These results suggest that NDP52 plays a key role in autophagy-mediated degradation of phosphorylated tau in vivo.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1038/ncomms4496

Cites

6 of 6 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Aggregated tau or tau phosphorylated at Ser262/356 is degraded by the autophagy-lysosome system.

    “The majority of tau species (including tau lacking phosphorylation at Ser262/356) are degraded by the proteasome [20], while aggregated tau or tau phosphorylated at Ser262/356 is degraded by the autophagy-lysosome system [79–84].”

    From Stabilization of Microtubule-Unbound Tau via Tau Phosphorylation at Ser262/356 by Par-1/MARK Contributes to Augmentation of AD-Related Phosphorylation and Aβ42-Induced Tau Toxicity (2016) · cites this paper as [84]

    The Results ('Autophagy mediates the degradation of phosphorylated tau'; page unavailable) show that blocking autophagy or lysosomal function attenuated phosphorylated-tau degradation. The Discussion reports reduced Ser262/356-phosphorylated tau after Nrf2 activation or NDP52 overexpression. The Results ('NDP52 decreases sarkosyl-insoluble tau in AD cases'; page unavailable) link NDP52 to less insoluble tau, but suggest prevention of aggregation through phosphorylated-tau clearance rather than demonstrating degradation of already aggregated tau. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 47

  1. [3]Ittner LM Gotz J Amyloid-beta and tau--a toxic pas de deux in Alzheimer's disease Nat Rev Neurosci 2011 12 65 72 21193853
  2. [4]Gong CX Grundke-Iqbal I Iqbal K Targeting tau protein in Alzheimer's disease Drugs Aging 2010 27 351 365 20450234
  3. [5]Zhang JY Liu SJ Li HL Wang JZ Microtubule-associated protein tau is a substrate of ATP/Mg(2+)-dependent proteasome protease system J Neural Transm 2005 112 547 555 15372326
  4. [6]David DC Proteasomal degradation of tau protein J Neurochem 2002 83 176 185 12358741
  5. [7]Carrettiero DC Hernandez I Neveu P Papagiannakopoulos T Kosik KS The cochaperone BAG2 sweeps paired helical filament-insoluble tau from the microtubule J Neurosci 2009 29 2151 2161 19228967 PMC2768429
  6. [8]Dickey CA The high-affinity HSP90-CHIP complex recognizes and selectively degrades phosphorylated tau client proteins J Clin Invest 2007 117 648 658 17304350 PMC1794119
  7. [9]Delobel P Proteasome inhibition and Tau proteolysis: an unexpected regulation FEBS Lett 2005 579 1 5 15620682 PMC7130380
  8. [10]Feuillette S Tau is not normally degraded by the proteasome J Neurosci Res 2005 80 400 405 15795929
  9. [11]Hamano T Autophagic-lysosomal perturbation enhances tau aggregation in transfectants with induced wild-type tau expression Eur J Neurosci 2008 27 1119 1130 18294209
  10. [12]Berger Z Rapamycin alleviates toxicity of different aggregate-prone proteins Hum Mol Genet 2006 15 433 442 16368705
  11. [14]Dolan PJ Johnson GV A caspase cleaved form of tau is preferentially degraded through the autophagy pathway J Biol Chem 2010 285 21978 21987 20466727 PMC2903354
  12. [15]Kruger U Wang Y Kumar S Mandelkow EM Autophagic degradation of tau in primary neurons and its enhancement by trehalose Neurobiol Aging 2011 22169203
  13. [16]Khurana V Lysosomal dysfunction promotes cleavage and neurotoxicity of tau in vivo PLoS Genet 2010 6 e1001026 20664788 PMC2904797
  14. [17]Shimada K Long-term oral lithium treatment attenuates motor disturbance in tauopathy model mice: implications of autophagy promotion Neurobiol Dis 2012 46 101 108 22249108
  15. [18]Clague MJ Urbe S Ubiquitin: same molecule, different degradation pathways Cell 2010 143 682 685 21111229
  16. [19]Johansen T Lamark T Selective autophagy mediated by autophagic adapter proteins Autophagy 2011 7 279 296 21189453 PMC3060413
  17. [20]Salminen A Emerging role of p62/sequestosome-1 in the pathogenesis of Alzheimer's disease Prog Neurobiol 2012 96 87 95 22138392
  18. [21]Komatsu M The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1 Nat Cell Biol 2010 12 213 223 20173742
  19. [22]Jain A p62/SQSTM1 is a target gene for transcription factor NRF2 and creates a positive feedback loop by inducing antioxidant response element-driven gene transcription J Biol Chem 2010 285 22576 22591 20452972 PMC2903417
  20. [23]Ramesh Babu J Genetic inactivation of p62 leads to accumulation of hyperphosphorylated tau and neurodegeneration J Neurochem 2008 106 107 120 18346206
  21. [24]Kirkin V A role for NBR1 in autophagosomal degradation of ubiquitinated substrates Mol Cell 2009 33 505 516 19250911
  22. [25]Wenger T Autophagy inhibition promotes defective neosynthesized proteins storage in ALIS, and induces redirection toward proteasome processing and MHCI-restricted presentation Autophagy 2012 8 22377621
  23. [26]D'Agostino C Nogalska A Cacciottolo M Engel WK Askanas V Abnormalities of NBR1, a novel autophagy-associated protein, in muscle fibers of sporadic inclusion-body myositis Acta Neuropathol 2011 122 627 636 21935636
  24. [27]Mostowy S p62 and NDP52 proteins target intracytosolic Shigella and Listeria to different autophagy pathways J Biol Chem 2011 286 26987 26995 21646350 PMC3143657
  25. [28]Thurston TL Ryzhakov G Bloor S von Muhlinen N Randow F The TBK1 adaptor and autophagy receptor NDP52 restricts the proliferation of ubiquitin-coated bacteria Nat Immunol 2009 10 1215 1221 19820708
  26. [29]Inomata M Niida S Shibata K Into T Regulation of Toll-like receptor signaling by NDP52-mediated selective autophagy is normally inactivated by A20 Cell Mol Life Sci 2012 69 963 979 21964925 PMC3285758
  27. [31]Kanninen K White AR Koistinaho J Malm T Targeting Glycogen Synthase Kinase-3beta for Therapeutic Benefit against Oxidative Stress in Alzheimer's Disease: Involvement of the Nrf2-ARE Pathway Int J Alzheimers Dis 2011 2011 985085 21629716 PMC3100734
  28. [32]Kensler TW Wakabayashi N Biswal S Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway Annu Rev Pharmacol Toxicol 2007 47 89 116 16968214
  29. [33]Kanninen K Intrahippocampal injection of a lentiviral vector expressing Nrf2 improves spatial learning in a mouse model of Alzheimer's disease Proc Natl Acad Sci U S A 2009 106 16505 16510 19805328 PMC2752553
  30. [34]Hur W Gray NS Small molecule modulators of antioxidant response pathway Curr Opin Chem Biol 2011 15 162 173 21195017
  31. [35]Liu F Grundke-Iqbal I Iqbal K Gong CX Contributions of protein phosphatases PP1, PP2A, PP2B and PP5 to the regulation of tau phosphorylation Eur J Neurosci 2005 22 1942 1950 16262633
  32. [36]Sontag E Nunbhakdi-Craig V Lee G Bloom GS Mumby MC Regulation of the phosphorylation state and microtubule-binding activity of Tau by protein phosphatase 2A Neuron 1996 17 1201 1207 8982166
  33. [37]Klionsky DJ Elazar Z Seglen PO Rubinsztein DC Does bafilomycin A1 block the fusion of autophagosomes with lysosomes? Autophagy 2008 4 849 950 18758232
  34. [38]Thurston TL Wandel MP von Muhlinen N Foeglein A Randow F Galectin 8 targets damaged vesicles for autophagy to defend cells against bacterial invasion Nature 2012 482 414 418 22246324 PMC3343631
  35. [39]Sarkar S Davies JE Huang Z Tunnacliffe A Rubinsztein DC Trehalose, a novel mTOR-independent autophagy enhancer, accelerates the clearance of mutant huntingtin and alpha-synuclein J Biol Chem 2007 282 5641 5652 17182613
  36. [40]Watanabe Y Tanaka M p62/SQSTM1 in autophagic clearance of a non-ubiquitylated substrate J Cell Sci 2011 124 2692 2701 21771882
  37. [41]Steinhilb ML S/P and T/P phosphorylation is critical for tau neurotoxicity in Drosophila J Neurosci Res 2007 85 1271 1278 17335084
  38. [42]Berger Z Accumulation of pathological tau species and memory loss in a conditional model of tauopathy J Neurosci 2007 27 3650 3662 17409229 PMC6672413
  39. [43]Brunden KR Trojanowski JQ Lee VM Evidence that non-fibrillar tau causes pathology linked to neurodegeneration and behavioral impairments J Alzheimers Dis 2008 14 393 399 18688089 PMC2789426
  40. [45]Shimura H Schwartz D Gygi SP Kosik KS CHIP-Hsc70 complex ubiquitinates phosphorylated tau and enhances cell survival J Biol Chem 2004 279 4869 4876 14612456
  41. [46]Dickey CA Deletion of the ubiquitin ligase CHIP leads to the accumulation, but not the aggregation, of both endogenous phospho- and caspase-3-cleaved tau species J Neurosci 2006 26 6985 6996 16807328 PMC6673930
  42. [47]Dickey CA HSP induction mediates selective clearance of tau phosphorylated at proline-directed Ser/Thr sites but not KXGS (MARK) sites FASEB J 2006 20 753 755 16464956
  43. [48]Watson RO Manzanillo PS Cox JS Extracellular M. tuberculosis DNA targets bacteria for autophagy by activating the host DNA-sensing pathway Cell 2012 150 803 815 22901810 PMC3708656
  44. [49]Cho JH Johnson GV Glycogen synthase kinase 3 beta induces caspase-cleaved tau aggregation in situ J Biol Chem 2004 279 54716 54723 15494420
  45. [50]Cho JH Johnson GV Glycogen synthase kinase 3beta phosphorylates tau at both primed and unprimed sites. Differential impact on microtubule binding J Biol Chem 2003 278 187 193 12409305
  46. [52]Bongarzone ER Two neuronal cell lines expressing the myelin basic protein gene display differences in their in vitro survival and in their response to glia J Neurosci Res 1998 54 309 319 9819136
  47. [53]Kress GJ Dineley KE Reynolds IJ The relationship between intracellular free iron and cell injury in cultured neurons, astrocytes, and oligodendrocytes J Neurosci 2002 22 5848 5855 12122047 PMC6757914

Cited by

Sorted by citations

Authors
Jo, C., Gundemir, S., Pritchard, S., Jin, Y. N., Rahman, I., & Johnson, G. V. W.
Affiliations
University of Rochester Medicine (US)
Corresponding author
Johnson, Gail V. W.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2014-03-25
Volume
5
Issue
1
Pages
3496-3496
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/ncomms4496
PMC
PMC3990284
OpenAlex
W1990271214
Cited by
323
References
6
Citations by year
2026: 21 · 2025: 23 · 2024: 22 · 2023: 24 · 2022: 23 · 2021: 31 · 2020: 33 · 2019: 24 · 2018: 28 · 2017: 32 · 2016: 27 · 2015: 25 · 2014: 10
FWCI
19.51
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
Funders
  • Universitetet i Tromsø
  • Michigan State University
  • University of Rochester
  • University College Dublin
  • National Institutes of Health
  • College of Engineering, Michigan State University
  • University of California, Los Angeles
  • Medical Center, University of Rochester
  • Medical Research Council
  • RIKEN
  • National Institute of Neurological Disorders and Stroke (NS076789, R21NS076789)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
Keywords
Nrf2, NDP52, phosphorylated tau, autophagy, Alzheimer's disease, antioxidant response element, oxidative stress, tau clearance, sarkosyl-insoluble tau, Nrf2 knockout mice, neurons
MeSH terms
Aged, Aged, 80 and over, Alzheimer Disease, Animals, Autophagy, Brain, Cerebral Cortex, Female, Hippocampus, Humans, Male, Nerve Tissue Proteins, Neurons, Nuclear Proteins, Phosphorylation, RNA, Messenger, tau Proteins, Receptors, Cytoplasmic and Nuclear, Mice, Knockout, Oxidative Stress, Reverse Transcriptase Polymerase Chain Reaction, Maf Transcription Factors, NF-E2-Related Factor 2, Mice, Rats, HEK293 Cells

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review