The amino terminus of tau inhibits kinesin-dependent axonal transport: implications for filament toxicity.
The neuropathology of Alzheimer's disease (AD) and other tauopathies is characterized by filamentous deposits of the microtubule-associated protein tau, but the relationship between tau polymerization and neurotoxicity is unknown. Here, we examined effects of filamentous tau on fast axonal transport (FAT) using isolated squid axoplasm. Monomeric and filamentous forms of recombinant human tau were perfused in axoplasm, and their effects on kinesin- and dynein-dependent FAT rates were evaluated by video microscopy. Although perfusion of monomeric tau at physiological concentrations showed no effect, tau filaments at the same concentrations selectively inhibited anterograde (kinesin-dependent) FAT, triggering the release of conventional kinesin from axoplasmic vesicles. Pharmacological experiments indicated that the effect of tau filaments on FAT is mediated by protein phosphatase 1 (PP1) and glycogen synthase kinase-3 (GSK-3) activities. Moreover, deletion analysis suggested that these effects depend on a conserved 18-amino-acid sequence at the amino terminus of tau. Interestingly, monomeric tau isoforms lacking the C-terminal half of the molecule (including the microtubule binding region) recapitulated the effects of full-length filamentous tau. Our results suggest that pathological tau aggregation contributes to neurodegeneration by altering a regulatory pathway for FAT.
LaPointe
Nichole E
NE
Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
Morfini
Gerardo
G
Pigino
Gustavo
G
Gaisina
Irina N
IN
Kozikowski
Alan P
AP
Binder
Lester I
LI
Brady
Scott T
ST
D000818:Animals; D001370:Axonal Transport / Q000502:physiology*; D003599:Cytoskeleton / Q000378:metabolism; D049832:Decapodiformes; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D016547:Kinesins / Q000378:metabolism*; D008870:Microtubules / Q000378:metabolism; D020033:Protein Isoforms / Q000737:chemistry / Q000378:metabolism; D054645:Protein Phosphatase 1 / Q000378:metabolism; D016875:tau Proteins / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity*
D020033:Protein Isoforms; D016875:tau Proteins; D038362:Glycogen Synthase Kinase 3; D054645:Protein Phosphatase 1; D016547:Kinesins
Biochim Biophys Acta. 2005 Jan 3;1739(2-3):260-7
15615644
J Cell Biol. 2006 Nov 20;175(4):541-6
17101697
J Am Chem Soc. 2007 Jul 4;129(26):8328-32
17552518
J Neurobiol. 1999 Jul;40(1):89-102
10398074
Ann Neurol. 2002 Apr;51(4):525-30
11921059
J Biol Chem. 1994 May 20;269(20):14566-74
7514173
EMBO J. 2004 Jun 2;23(11):2235-45
15152189
Anal Biochem. 1994 Aug 1;220(2):397-402
7978284
Methods Enzymol. 1991;201:389-98
1658556
J Cell Biol. 1995 Dec;131(5):1327-40
8522593
J Cell Sci. 2000 Nov;113 Pt 21:3737-45
11034902
Biochemistry. 2006 Oct 24;45(42):12859-66
17042504
Trends Mol Med. 2005 Feb;11(2):64-70
15694868
Nature. 1985 Sep 5-11;317(6032):73-5
2412134
J Biol Chem. 2002 Apr 5;277(14):11933-40
11812770
J Neurosci. 2002 Jun 1;22(11):4335-45
12040039
Curr Alzheimer Res. 2005 Jan;2(1):3-18
15977985
J Neurochem. 2004 Jul;90(2):340-51
15228591
Biochemistry. 2003 Feb 25;42(7):2252-7
12590615
Proc Natl Acad Sci U S A. 2003 Aug 19;100(17):10032-7
12888622
Proc Natl Acad Sci U S A. 2000 May 9;97(10):5129-34
10805776
Neurobiol Aging. 2005 Jul;26(7):1015-22
15748781
Adv Protein Chem. 2005;71:257-98
16230114
J Neurosci Res. 2007 Sep;85(12):2620-30
17265463
Eur J Biochem. 2002 Jan;269(1):148-56
11784308
J Cell Biol. 1984 Jun;98(6):2064-76
6202702
Neuron. 1988 Nov;1(9):817-25
2483104
Proc Natl Acad Sci U S A. 2007 Feb 13;104(7):2442-7
17287338
Neuron. 1989 Jun;2(6):1615-24
2516729
J Biol Chem. 1998 Aug 21;273(34):21901-8
9705329
J Biol Chem. 1996 Dec 20;271(51):32789-95
8955115
Biochemistry. 1994 Aug 16;33(32):9511-22
8068626
Cell Death Differ. 2004 Feb;11(2):217-30
14615799
Biochemistry. 2003 Jul 15;42(27):8325-31
12846581
Ann Neurol. 2002 Oct;52(4):511-6
12325083
J Cell Biol. 1985 Nov;101(5 Pt 1):1799-807
2997236
J Cell Sci. 1997 Mar;110 ( Pt 6):789-800
9099953
Eur J Pharmacol. 2006 Sep 1;545(1):11-21
16887118
Biochemistry. 1999 Nov 9;38(45):14851-9
10555967
J Biol Chem. 1994 Sep 30;269(39):24290-7
7929085
Proc Natl Acad Sci U S A. 2007 Jan 2;104(1):87-92
17190808
J Cell Biol. 1998 Nov 2;143(3):777-94
9813097
Biochemistry. 2003 Dec 30;42(51):15009-17
14690409
J Cell Biol. 1993 Jan;120(2):467-76
7678421
J Neurosci. 2004 Sep 8;24(36):7895-902
15356202
Exp Neurol. 2002 Oct;177(2):475-93
12429193
EMBO J. 2002 Feb 1;21(3):281-93
11823421
Biochemistry. 2006 Apr 4;45(13):4314-26
16566606
J Neurosci. 2004 Mar 3;24(9):2304-12
14999081
J Neurosci. 2003 Jun 1;23(11):4499-508
12805290
Neuromolecular Med. 2002;2(2):89-99
12428805
Cell Motil. 1985;5(2):81-101
2580632
Biochim Biophys Acta. 2005 Jan 3;1739(2-3):216-23
15615640
EMBO J. 2002 Sep 16;21(18):4896-905
12234929
Nat Neurosci. 2006 Jul;9(7):907-16
16751763
Biochim Biophys Acta. 2005 Jan 3;1739(2-3):323-30
15615649
Neuron. 2007 Feb 1;53(3):337-51
17270732
Biochemistry. 2006 Feb 21;45(7):2283-93
16475817
Proc Natl Acad Sci U S A. 2006 Feb 21;103(8):2892-7
16477009
J Cell Biol. 1997 Sep 8;138(5):1067-75
9281584