Kinesin-1 transport reductions enhance human tau hyperphosphorylation, aggregation and neurodegeneration in animal models of tauopathies.
Neurodegeneration induced by abnormal hyperphosphorylation and aggregation of the microtubule-associated protein tau defines neurodegenerative tauopathies. Destabilization of microtubules by loss of tau function and filament formation by toxic gain of function are two mechanisms suggested for how abnormal tau triggers neuronal loss. Recent experiments in kinesin-1 deficient mice suggested that axonal transport defects can initiate biochemical changes that induce activation of axonal stress kinase pathways leading to abnormal tau hyperphosphorylation. Here we show using Drosophila and mouse models of tauopathies that reductions in axonal transport can exacerbate human tau protein hyperphosphorylation, formation of insoluble aggregates and tau-dependent neurodegeneration. Together with previous work, our results suggest that non-lethal reductions in axonal transport, and perhaps other types of minor axonal stress, are sufficient to induce and/or accelerate abnormal tau behavior characteristic of Alzheimer's disease and other neurodegenerative tauopathies.
Falzone
Tomás L
TL
Department of Cellular and Molecular Medicine, Howard Hughes Medical Institute, University of California-San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
Gunawardena
Shermali
S
McCleary
David
D
Reis
Gerald F
GF
Goldstein
Lawrence S B
LS
D000818:Animals; D030801:Animals, Genetically Modified; D001370:Axonal Transport / Q000502:physiology; D003599:Cytoskeleton / Q000378:metabolism; D004195:Disease Models, Animal; D004330:Drosophila; D005260:Female; D006801:Humans; D016547:Kinesins / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D009410:Nerve Degeneration / Q000378:metabolism* / Q000473:pathology*; D010766:Phosphorylation; D024801:Tauopathies / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D016875:tau Proteins / Q000378:metabolism*
C054369:MAPT protein, human; D016875:tau Proteins; D016547:Kinesins
J Gerontol A Biol Sci Med Sci. 1999 Oct;54(10):B407-17
10568523
Science. 2005 Feb 25;307(5713):1282-8
15731448
FEBS Lett. 1997 Jun 2;409(1):57-62
9199504
Proc Natl Acad Sci U S A. 1993 Jun 1;90(11):5066-70
8506352
Neuron. 2001 Nov 8;32(3):389-401
11709151
Proc Natl Acad Sci U S A. 1998 Jun 23;95(13):7737-41
9636220
J Neuropathol Exp Neurol. 2006 May;65(5):455-64
16772869
Am J Pathol. 2000 Jul;157(1):331-9
10880403
J Cell Sci. 1999 Jul;112 ( Pt 14):2355-67
10381391
Annu Rev Neurosci. 2008;31:151-73
18558852
Nat Genet. 2000 Aug;25(4):402-5
10932182
Hum Mol Genet. 2008 Nov 15;17(22):3474-86
18694898
Curr Biol. 1999 May 6;9(9):489-92
10322116
Annu Rev Biochem. 2006;75:607-27
16756504
J Neural Transm (Vienna). 2001;108(12):1397-415
11810404
J Neurosci. 1997 Sep 15;17(18):7053-9
9278541
J Neurosci. 2009 May 6;29(18):5758-67
19420244
Ann Neurol. 1998 Jun;43(6):815-25
9629852
J Biol Chem. 1984 Apr 25;259(8):5301-5
6425287
J Cell Biol. 1998 Apr 20;141(2):443-54
9548722
J Neurosci Res. 2009 Feb;87(2):440-51
18798283
Acta Neuropathol. 1991;82(4):239-59
1759558
Neuron. 2003 Oct 9;40(2):415-25
14556718
Neuroimage. 2007;37 Suppl 1:S37-46
17600729
Annu Rev Neurosci. 2001;24:1121-59
11520930
Neurodegener Dis. 2007;4(2-3):236-53
17596718
Curr Alzheimer Res. 2008 Aug;5(4):375-84
18690834
Neuromolecular Med. 2002;2(2):131-50
12428808
J Neurol. 1996 Mar;243(3):231-4
8936352
Neuroreport. 1994 Nov 21;5(17):2358-62
7533559
J Neurochem. 2002 Dec;83(6):1498-508
12472903
Nat Rev Neurosci. 2007 Sep;8(9):663-72
17684513
Neuron. 1993 Jun;10(6):1089-99
8318230
J Neuropathol Exp Neurol. 1997 Sep;56(9):965-73
9291938
Nat Neurosci. 2009 Jul;12(7):864-71
19525941
Science. 2001 Aug 24;293(5534):1487-91
11520987
Curr Opin Neurol. 2003 Jun;16(3):267-73
12858061
Science. 2001 Aug 24;293(5534):1491-5
11520988
J Neurochem. 2004 Jul;90(2):352-8
15228592
Acta Neuropathol. 2000 May;99(5):469-81
10805089
J Neurosci. 2005 Nov 16;25(46):10637-47
16291936
J Cell Biol. 1998 Nov 2;143(3):777-94
9813097
Nat Rev Neurosci. 2008 Jul;9(7):532-44
18568014
FASEB J. 2008 Sep;22(9):3186-95
18511549
J Cell Biol. 2002 Mar 18;156(6):1051-63
11901170
J Neuropathol Exp Neurol. 2001 Dec;60(12):1190-7
11764091
Neurology. 2006 Jun 27;66(12):1845-9
16801648
Brain Res Brain Res Rev. 2000 Aug;33(1):95-130
10967355
FEBS Lett. 1999 May 14;451(1):39-44
10356980
Eur J Neurosci. 2008 Jul;28(1):137-47
18662339
J Cell Biol. 2005 Feb 28;168(5):775-87
15738268
Nature. 1998 Jun 18;393(6686):702-5
9641683
J Alzheimers Dis. 2001 Feb;3(1):41-48
12214071
Neurobiol Dis. 1997;4(5):365-75
9440125
Science. 2008 Feb 22;319(5866):1086-9
18202255
Trends Genet. 2006 May;22(5):281-9
16567017
J Neurosci. 2005 Oct 12;25(41):9434-43
16221853
J Alzheimers Dis. 2008 Dec;15(4):541-53
19096155
J Neurocytol. 2005 Dec;34(6):397-410
16902761
J Neurosci. 2006 Jun 28;26(26):6985-96
16807328
Science. 2001 Jul 27;293(5530):711-4
11408621
Nat Neurosci. 2006 Jul;9(7):907-16
16751763