Differential effect of three-repeat and four-repeat tau on mitochondrial axonal transport.
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.
Stoothoff
Will
W
MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
Jones
Phillip B
PB
Spires-Jones
Tara L
TL
Joyner
Daniel
D
Chhabra
Ekta
E
Bercury
Kathryn
K
Fan
Zhanyun
Z
Xie
Hong
H
Bacskai
Brian
B
Edd
Jon
J
Irimia
Daniel
D
Hyman
Bradley T
BT
D000818:Animals; D001370:Axonal Transport / Q000502:physiology*; D045744:Cell Line, Tumor; D002540:Cerebral Cortex / Q000166:cytology; D005910:Glioma; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D051379:Mice; D046210:Microfluidic Analytical Techniques; D008928:Mitochondria / Q000502:physiology*; D009474:Neurons / Q000166:cytology / Q000502:physiology*; D021381:Protein Transport / Q000502:physiology; D012091:Repetitive Sequences, Nucleic Acid / Q000502:physiology; D024801:Tauopathies / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D014162:Transfection; D016875:tau Proteins / Q000235:genetics* / Q000378:metabolism*
C054369:MAPT protein, human; D016875:tau Proteins; D049452:Green Fluorescent Proteins
J Cell Biol. 2004 Oct 11;167(1):99-110
15466480
Science. 2005 Jul 15;309(5733):476-81
16020737
Neuropathology. 2006 Oct;26(5):484-90
17080729
Neuron. 1989 Apr;2(4):1389-97
2560640
J Neurosci. 2007 Mar 14;27(11):2896-907
17360912
Biophys J. 2008 Sep 15;95(6):3079-99
18757564
J Biol Chem. 2009 Mar 6;284(10):6021-5
18948254
Proc Natl Acad Sci U S A. 2007 Jan 2;104(1):87-92
17190808
J Cell Biol. 2002 Mar 18;156(6):1051-63
11901170
Cell Motil Cytoskeleton. 2008 Feb;65(2):89-99
18000878
Science. 2008 Feb 22;319(5866):1086-9
18202255
J Cell Sci. 1999 Jul;112 ( Pt 14):2355-67
10381391
Traffic. 2008 Jun;9(6):882-92
18373727
J Neurochem. 2007 Nov;103(3):1228-36
17727636
Acta Neuropathol. 2007 Nov;114(5):471-9
17721707
Brain Pathol. 2007 Jan;17(1):63-73
17493040
Proc Natl Acad Sci U S A. 2003 Aug 19;100(17):10032-7
12888622
Proc Natl Acad Sci U S A. 2008 Oct 14;105(41):15997-6002
18832465
J Neurochem. 2006 Aug;98(4):993-1006
16787410
J Cell Biol. 1991 Nov;115(3):717-30
1918161
Am J Pathol. 2006 May;168(5):1598-607
16651626
EMBO J. 1990 Dec;9(13):4225-30
2124967
J Cell Biol. 1998 Nov 2;143(3):777-94
9813097
Neurobiol Aging. 2003 Dec;24(8):1079-85
14643379
Nat Methods. 2005 Aug;2(8):599-605
16094385
Trends Neurosci. 2009 Mar;32(3):150-9
19162340
Neuron. 1989 Oct;3(4):519-26
2484340
J Neurosci Res. 2000 Sep 1;61(5):515-23
10956421
EMBO J. 2002 Sep 16;21(18):4896-905
12234929
Neuropathology. 2006 Oct;26(5):471-4
17080727
Cell Struct Funct. 1996 Oct;21(5):283-95
9118234
Brain Pathol. 2007 Jan;17(1):83-90
17493042
Ann N Y Acad Sci. 2000;920:63-73
11193178