The tau N279K exon 10 splicing mutation recapitulates frontotemporal dementia and parkinsonism linked to chromosome 17 tauopathy in a mouse model.
Intracellular tau deposits are characteristic of several neurodegenerative disorders called tauopathies. The tau protein regulates the stability and assembly of microtubules by binding to microtubules through three or four microtubule-binding repeats (3R and 4R). The number of microtubule-binding repeats is determined by the inclusion or exclusion of the second microtubule-binding repeat encoded by exon 10 of the TAU gene. TAU gene mutations that alter the inclusion of exon 10, and hence the 4R:3R ratio, are causal in the tauopathy frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). A mutation located in exon 10 has been identified in several FTDP-17 families that present with increased exon 10 inclusion in both mRNA and protein, parkinsonism, movement disorders, and dementia. We have engineered a human tau minigene construct that was designed to allow alternative splicing of the tau exon 10. Here we demonstrate that transgenic mice expressing human tau protein with this mutation develop neurodegeneration as result of aberrant splicing. The mice recapitulate many of the disease hallmarks that are seen in patients with this mutation, including increased tau exon 10 inclusion in both mRNA and protein, motor and behavioral deficits, and tau protein accumulation in neurons and tufted astrocytes. Furthermore, these mice present with degeneration of the nigrostriatal dopaminergic pathway, suggesting a possible mechanism for parkinsonism in FTDP-17. Additionally, activated caspase-3 immunoreactivity in both neurons and astrocytes implicates the involvement of the apoptotic pathway in the pathology of these mice.
Dawson
Hana N
HN
Division of Neurology, Duke University, Durham, North Carolina 27710, USA. dawso009@mc.duke.edu
Cantillana
Viviana
V
Chen
Liling
L
Vitek
Michael P
MP
D000367:Age Factors; D000704:Analysis of Variance; D000818:Animals; D001216:Asparagine / Q000235:genetics*; D001522:Behavior, Animal; D002490:Central Nervous System / Q000473:pathology; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics*; D003704:Dementia / Q000235:genetics*; D004622:Embryo, Mammalian; D005091:Exons / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D008239:Lysine / Q000235:genetics*; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D008958:Models, Molecular; D009043:Motor Activity / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D020734:Parkinsonian Disorders / Q000235:genetics*; D012326:RNA Splicing / Q000235:genetics*; D016875:tau Proteins / Q000235:genetics*
D009419:Nerve Tissue Proteins; D016875:tau Proteins; D001216:Asparagine; D008239:Lysine
J Neurochem. 1999 Mar;72(3):1243-9
10037497
Hum Mol Genet. 1999 Apr;8(4):711-5
10072441
FEBS Lett. 1999 Mar 26;447(2-3):195-9
10214944
Proc Natl Acad Sci U S A. 1999 May 11;96(10):5598-603
10318930
Brain Res. 1999 Jun 12;831(1-2):301-5
10412011
Acta Neuropathol. 1999 Jul;98(1):62-77
10412802
Acta Neuropathol. 1999 Sep;98(3):251-6
10483782
Neurology. 1999 Sep 11;53(4):864-8
10489057
Biochemistry. 1999 Nov 9;38(45):14851-9
10555967
Proc Natl Acad Sci U S A. 1975 May;72(5):1858-62
1057175
Neurosci Lett. 1999 Nov 19;275(3):183-6
10580705
Acta Neuropathol. 2000 Jan;99(1):73-80
10651031
Ann Neurol. 2000 Mar;47(3):374-7
10716259
J Biol Chem. 2000 Jun 9;275(23):17700-9
10748133
Neurobiol Dis. 2000 Apr;7(2):87-98
10783293
Neurology. 2000 May 9;54(9):1787-95
10802785
Biochemistry. 2000 May 23;39(20):6136-44
10821687
J Neurochem. 2000 Aug;75(2):624-33
10899937
Brain Res. 2000 Aug 25;874(2):123-30
10960596
Brain Res Brain Res Rev. 2000 Aug;33(1):95-130
10967355
J Biol Chem. 2000 Dec 8;275(49):38182-9
10984497
Bull Acad Natl Med. 2000;184(4):799-809; discussion 809-11
10989564
Nature. 2000 Dec 21-28;408(6815):982-5
11140686
Neurobiol Aging. 2001 Jan-Feb;22(1):89-107
11164280
J Cell Sci. 2001 Mar;114(Pt 6):1179-87
11228161
Acta Neuropathol. 2001 Feb;101(2):167-73
11271372
Neurobiol Aging. 2001 May-Jun;22(3):377-85
11378242
FEBS Lett. 2001 Jun 8;498(2-3):179-82
11412852
Neurology. 2001 Jun 26;56(12):1702-6
11425937
Neurosci Lett. 2001 Oct 5;311(3):145-8
11578815
Ann Neurol. 2001 Oct;50(4):494-502
11601500
Acta Neuropathol. 2002 Jan;103(1):82-7
11837750
Methods. 2001 Dec;25(4):402-8
11846609
J Cell Biol. 2002 Mar 18;156(6):1051-63
11901170
J Biol Chem. 2002 Jul 19;277(29):26587-99
12000767
Arch Neurol. 2002 Jun;59(6):943-50
12056930
J Neuropathol Exp Neurol. 2002 Jun;61(6):547-56
12071638
Mov Disord. 2002 May;17(3):550-6
12112206
Acta Neuropathol. 2002 Oct;104(4):398-402
12200627
Science. 2002 Oct 11;298(5592):416-9
12376702
J Biol Chem. 2003 Jan 17;278(3):1511-7
12421814
Neurology. 2002 Dec 10;59(11):1791-3
12473774
Cell Mol Life Sci. 2002 Oct;59(10):1668-80
12475178
Auton Neurosci. 2002 Nov 29;102(1-2):71-7
12492138
Brain Res Dev Brain Res. 2003 May 14;142(2):121-7
12711363
J Alzheimers Dis. 2003 Apr;5(2):65-77
12719624
Arch Neurol. 2003 May;60(5):698-702
12756133
Acta Neuropathol. 2003 Sep;106(3):251-60
12802605
J Biol Chem. 2003 Aug 29;278(35):33298-304
12805366
Biochemistry. 2003 Jul 15;42(27):8325-31
12846581
Neurology. 2003 Jul 8;61(1):102-4
12847166
Proc Natl Acad Sci U S A. 2003 Aug 5;100(16):9548-53
12886013
Proc Natl Acad Sci U S A. 2003 Aug 19;100(17):10032-7
12888622
Neurosci Lett. 1992 Jan 20;135(1):99-102
1371861
Acta Neuropathol. 1992;84(3):265-72
1384266
Ann Neurol. 1992 Sep;32(3):312-20
1416801
Arch Neurol. 2003 Oct;60(10):1454-6
14568818
J Neurosci. 2003 Nov 19;23(33):10662-71
14627651
Biochemistry. 2003 Dec 30;42(51):15009-17
14690409
Neurology. 2003 Dec 23;61(12):1766-73
14694044
Ann Neurol. 2004 Mar;55(3):329-34
14991810
Arch Neurol. 2004 Mar;61(3):398-406
15023818
Neuropathology. 2004 Mar;24(1):60-5
15068174
Hum Mol Genet. 2004 Jun 15;13(12):1267-74
15115761
J Clin Invest. 2004 Jul;114(1):121-30
15232619
Hum Mutat. 2004 Oct;24(4):277-95
15365985
Nat Med. 2004 Oct;10(10):1055-63
15459709
Biochim Biophys Acta. 2005 Jan 3;1739(2-3):104-15
15615630
EMBO J. 1992 Apr;11(4):1593-7
1563356
J Biol Chem. 2005 Apr 8;280(14):13520-8
15671021
J Neuropathol Exp Neurol. 2005 Feb;64(2):104-12
15751224
J Neurosci. 2005 Apr 6;25(14):3539-50
15814784
Acta Neuropathol. 2005 Aug;110(2):135-44
15986225
Neurobiol Dis. 2005 Oct;20(1):64-73
16137567
Mol Ther. 2006 Mar;13(3):517-27
16325474
Neurosci Lett. 1990 Nov 13;119(2):182-6
1704110
Neurobiol Aging. 1991 Jul-Aug;12(4):357-61
1720514
Anat Rec. 1991 Dec;231(4):482-97
1793176
Acta Neuropathol. 1991;81(6):603-9
1882636
J Cell Biol. 1991 Nov;115(3):717-30
1918161
Nature. 1990 Feb 1;343(6257):461-3
2105469
EMBO J. 1990 Dec;9(13):4225-30
2124967
EMBO J. 1989 Feb;8(2):393-9
2498079
Mol Cell Biol. 1989 Apr;9(4):1381-8
2498649
Mol Cell Biol. 1989 Apr;9(4):1389-96
2498650
J Cell Biol. 1985 Oct;101(4):1371-8
3930508
J Cell Biol. 1984 Mar;98(3):1090-7
6421824
Acta Neuropathol. 1993;85(3):308-15
7681616
J Neurotrauma. 1994 Apr;11(2):187-96
7932797
Neuron. 1994 Oct;13(4):989-1002
7946342
Biochemistry. 1994 Aug 16;33(32):9511-22
8068626
Proc Natl Acad Sci U S A. 1994 May 24;91(11):4766-70
8197133
Annu Rev Neurosci. 1994;17:267-310
8210176
Acta Neuropathol. 1993;86(6):609-16
8310816
Brain Res Mol Brain Res. 1996 Jul;39(1-2):79-88
8804716
Ann Neurol. 1997 Jun;41(6):706-15
9189031
J Neural Transm Suppl. 1997;49:269-75
9266434
Proc Natl Acad Sci U S A. 1997 Oct 14;94(21):11456-60
9326631
Ann Neurol. 1998 Jun;43(6):815-25
9629852
J Neuropathol Exp Neurol. 1998 Jun;57(6):588-601
9630238
Proc Natl Acad Sci U S A. 1998 Jun 23;95(13):7737-41
9636220
Nature. 1998 Jun 18;393(6686):702-5
9641683
Arch Neurol. 1998 Aug;55(8):1122-4
9708963
FEBS Lett. 1998 Aug 21;433(3):201-4
9744794
Proc Natl Acad Sci U S A. 1998 Oct 27;95(22):13103-7
9789048
J Cell Biol. 1998 Nov 2;143(3):777-94
9813097
FEBS Lett. 1998 Oct 23;437(3):207-10
9824291
Science. 1998 Dec 4;282(5395):1914-7
9836646
Am J Pathol. 1999 Jan;154(1):1-6
9916910