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PMID: 19686388 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

Differential effect of three-repeat and four-repeat tau on mitochondrial axonal transport.

Journal of neurochemistry ·Vol. 111 ·No. 2 ·2009-10-00 ·Pages 417-27

Stoothoff W, Jones PB, Spires-Jones TL, Joyner D, Chhabra E, Bercury K, Fan Z, Xie H, Bacskai B, Edd J, Irimia D, Hyman BT

Abstract

Tau protein is present in six different splice forms in the human brain and interacts with microtubules via either 3 or 4 microtubule binding repeats. An increased ratio of 3 repeat to 4 repeat isoforms is associated with neurodegeneration in inherited forms of frontotemporal dementia. Tau over-expression diminishes axonal transport in several systems, but differential effects of 3 repeat and 4 repeat isoforms have not been studied. We examined the effects of tau on mitochondrial transport and found that both 3 repeat and 4 repeat tau change normal mitochondrial distribution within the cell body and reduce mitochondrial localization to axons; 4 repeat tau has a greater effect than 3 repeat tau. Further, we observed that the 3 repeat and 4 repeat tau cause different alterations in retrograde and anterograde transport dynamics with 3 repeat tau having a slightly stronger effect on axon transport dynamics. Our results indicate that tau-induced changes in axonal transport may be an underlying theme in neurodegenerative diseases associated with isoform specific changes in tau's interaction with microtubules.

MeSH Terms
Animals Axonal Transport/physiology Cell Line, Tumor Cerebral Cortex/cytology Glioma Green Fluorescent Proteins/genetics Humans Mice Microfluidic Analytical Techniques Mitochondria/physiology Neurons/cytology,physiology Protein Transport/physiology Repetitive Sequences, Nucleic Acid/physiology Tauopathies/genetics,metabolism,physiopathology Transfection tau Proteins/genetics,metabolism
Chemicals
MAPT protein, human tau Proteins Green Fluorescent Proteins
Authors & Affiliations
12 authors, click to expand affiliations / ORCID
Stoothoff Will
MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
Jones Phillip B
Spires-Jones Tara L
Joyner Daniel
Chhabra Ekta
Bercury Kathryn
Fan Zhanyun
Xie Hong
Bacskai Brian
Edd Jon
Irimia Daniel
Hyman Bradley T
References (33)
33 references, click to expand
  1. MARK/PAR1 kinase is a regulator of microtubule-dependent transport in axons.
    J Cell Biol. 2004 Oct 11;167(1):99-110 PMID: 15466480
  2. Tau suppression in a neurodegenerative mouse model improves memory function.
    Science. 2005 Jul 15;309(5733):476-81 PMID: 16020737
  3. Biochemistry and molecular biology of tauopathies.
    Neuropathology. 2006 Oct;26(5):484-90 PMID: 17080729
  4. Developmentally regulated expression of specific tau sequences.
    Neuron. 1989 Apr;2(4):1389-97 PMID: 2560640
  5. Missorting of tau in neurons causes degeneration of synapses that can be rescued by the kinase MARK2/Par-1.
    J Neurosci. 2007 Mar 14;27(11):2896-907 PMID: 17360912
  6. Measurement of instantaneous velocity vectors of organelle transport: mitochondrial transport and bioenergetics in hippocampal neurons.
    Biophys J. 2008 Sep 15;95(6):3079-99 PMID: 18757564
  7. Tau mutations in neurodegenerative diseases.
    J Biol Chem. 2009 Mar 6;284(10):6021-5 PMID: 18948254
  8. Multiple-motor based transport and its regulation by Tau.
    Proc Natl Acad Sci U S A. 2007 Jan 2;104(1):87-92 PMID: 17190808
  9. Tau blocks traffic of organelles, neurofilaments, and APP vesicles in neurons and enhances oxidative stress.
    J Cell Biol. 2002 Mar 18;156(6):1051-63 PMID: 11901170
  10. Tau inhibits anterograde axonal transport and perturbs stability in growing axonal neurites in part by displacing kinesin cargo: neurofilaments attenuate tau-mediated neurite instability.
    Cell Motil Cytoskeleton. 2008 Feb;65(2):89-99 PMID: 18000878
  11. Differential regulation of dynein and kinesin motor proteins by tau.
    Science. 2008 Feb 22;319(5866):1086-9 PMID: 18202255
  12. Tau regulates the attachment/detachment but not the speed of motors in microtubule-dependent transport of single vesicles and organelles.
    J Cell Sci. 1999 Jul;112 ( Pt 14):2355-67 PMID: 10381391
  13. Tuning microtubule-based transport through filamentous MAPs: the problem of dynein.
    Traffic. 2008 Jun;9(6):882-92 PMID: 18373727
  14. Single molecule profiling of tau gene expression in Alzheimer's disease.
    J Neurochem. 2007 Nov;103(3):1228-36 PMID: 17727636
  15. Increase in the relative expression of tau with four microtubule binding repeat regions in frontotemporal lobar degeneration and progressive supranuclear palsy brains.
    Acta Neuropathol. 2007 Nov;114(5):471-9 PMID: 17721707
  16. Hereditary frontotemporal dementia caused by Tau gene mutations.
    Brain Pathol. 2007 Jan;17(1):63-73 PMID: 17493040
  17. Caspase cleavage of tau: linking amyloid and neurofibrillary tangles in Alzheimer's disease.
    Proc Natl Acad Sci U S A. 2003 Aug 19;100(17):10032-7 PMID: 12888622
  18. Parkinsonism and impaired axonal transport in a mouse model of frontotemporal dementia.
    Proc Natl Acad Sci U S A. 2008 Oct 14;105(41):15997-6002 PMID: 18832465
  19. Do axonal defects in tau and amyloid precursor protein transgenic animals model axonopathy in Alzheimer's disease?
    J Neurochem. 2006 Aug;98(4):993-1006 PMID: 16787410
  20. Tau protein binds to microtubules through a flexible array of distributed weak sites.
    J Cell Biol. 1991 Nov;115(3):717-30 PMID: 1918161
  21. Region-specific dissociation of neuronal loss and neurofibrillary pathology in a mouse model of tauopathy.
    Am J Pathol. 2006 May;168(5):1598-607 PMID: 16651626
  22. Expression of separate isoforms of human tau protein: correlation with the tau pattern in brain and effects on tubulin polymerization.
    EMBO J. 1990 Dec;9(13):4225-30 PMID: 2124967
  23. Overexpression of tau protein inhibits kinesin-dependent trafficking of vesicles, mitochondria, and endoplasmic reticulum: implications for Alzheimer's disease.
    J Cell Biol. 1998 Nov 2;143(3):777-94 PMID: 9813097
  24. Clogging of axons by tau, inhibition of axonal traffic and starvation of synapses.
    Neurobiol Aging. 2003 Dec;24(8):1079-85 PMID: 14643379
  25. A microfluidic culture platform for CNS axonal injury, regeneration and transport.
    Nat Methods. 2005 Aug;2(8):599-605 PMID: 16094385
  26. Tau pathophysiology in neurodegeneration: a tangled issue.
    Trends Neurosci. 2009 Mar;32(3):150-9 PMID: 19162340
  27. Multiple isoforms of human microtubule-associated protein tau: sequences and localization in neurofibrillary tangles of Alzheimer's disease.
    Neuron. 1989 Oct;3(4):519-26 PMID: 2484340
  28. Transient oxidative stress in SH-SY5Y human neuroblastoma cells results in caspase dependent and independent cell death and tau proteolysis.
    J Neurosci Res. 2000 Sep 1;61(5):515-23 PMID: 10956421
  29. Single-molecule investigation of the interference between kinesin, tau and MAP2c.
    EMBO J. 2002 Sep 16;21(18):4896-905 PMID: 12234929
  30. Neuropathology of familial tauopathy.
    Neuropathology. 2006 Oct;26(5):471-4 PMID: 17080727
  31. Microtubule-associated proteins regulate microtubule function as the track for intracellular membrane organelle transports.
    Cell Struct Funct. 1996 Oct;21(5):283-95 PMID: 9118234
  32. Structural principles of tau and the paired helical filaments of Alzheimer's disease.
    Brain Pathol. 2007 Jan;17(1):83-90 PMID: 17493042
  33. Molecular genetics of chromosome 17 tauopathies.
    Ann N Y Acad Sci. 2000;920:63-73 PMID: 11193178
Article Info
Journal
Journal of neurochemistry
Abbr.
J Neurochem
ISSN
1471-4159
DOI
10.1111/j.1471-4159.2009.06316.x
Published
2009-10-00
Epub
2009-00-03
Pages
417-27
Language
English
Region
England
NLM ID
2985190R
PMCID
PMC2831412
Subset
IM
Grants
NIA NIH HHS · P30 AG062421 · United States
NIBIB NIH HHS · R01 EB000768 · United States
NIA NIH HHS · P50 AG005134 · United States
NIA NIH HHS · K99 AG033670 · United States
NIA NIH HHS · R01 AG008487-18S1 · United States
NIA NIH HHS · R01 AG026249 · United States
NIA NIH HHS · P50 AG005134-210027 · United States
NIBIB NIH HHS · P41 EB002503 · United States
NIA NIH HHS · P50 AG005134-268383 · United States
NIA NIH HHS · 2P50 AG05134 · United States
NIA NIH HHS · K99 AG033670-01A1 · United States
NIA NIH HHS · 1 R01 AG 026249 · United States
NIA NIH HHS · R01 AG008487 · United States
NIA NIH HHS · P50 AG005134-140021 · United States
NIBIB NIH HHS · EB00768 · United States
External Links
PubMed source DOI: 10.1111/j.1471-4159.2009.06316.x PMC Full Text View journal details
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