title: TDP-43 Proteinopathy and ALS: Insights into Disease Mechanisms and Therapeutic Targets.
abstract: Therapeutic options for patients with amyotrophic lateral sclerosis (ALS) are currently limited. However, recent studies show that almost all cases of ALS, as well as tau-negative frontotemporal dementia (FTD), share a common neuropathology characterized by the deposition of TAR-DNA binding protein (TDP)-43-positive protein inclusions, offering an attractive target for the design and testing of novel therapeutics. Here we demonstrate how diverse environmental stressors linked to stress granule formation, as well as mutations in genes encoding RNA processing proteins and protein degradation adaptors, initiate ALS pathogenesis via TDP-43. We review the progressive development of TDP-43 proteinopathy from cytoplasmic mislocalization and misfolding through to macroaggregation and the addition of phosphate and ubiquitin moieties. Drawing from cellular and animal studies, we explore the feasibility of therapeutics that act at each point in pathogenesis, from mitigating genetic risk using antisense oligonucleotides to modulating TDP-43 proteinopathy itself using small molecule activators of autophagy, the ubiquitin-proteasome system, or the chaperone network. We present the case that preventing the misfolding of TDP-43 and/or enhancing its clearance represents the most important target for effectively treating ALS and frontotemporal dementia.
authors: Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, de Crespigny Park, London, SE5 8AF, UK.
authors: Emma L
authors: EL
authors: Scotter
authors: Han-Jou
authors: HJ
authors: Chen
authors: Christopher E
authors: CE
authors: Shaw
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004777:Environment; D020868:Gene Silencing / Q000502:physiology; D006801:Humans; D009154:Mutation / Q000235:genetics; D057177:TDP-43 Proteinopathies / Q000235:genetics / Q000378:metabolism / Q000628:therapy
chemical_list: D004268:DNA-Binding Proteins; C000598624:TARDBP protein, human
references: Hum Mol Genet. 2013 Apr 15;22(8):1539-57
references: 23307927
references: J Neurosci. 2014 Mar 19;34(12):4167-74
references: 24647938
references: J Neurosci. 2010 Jan 13;30(2):639-49
references: 20071528
references: Ann Neurol. 2008 Jul;64(1):60-70
references: 18546284
references: J Biol Chem. 2011 Dec 30;286(52):44441-8
references: 22052911
references: Neuron. 2011 Oct 20;72(2):257-68
references: 21944779
references: Nature. 2011 Aug 21;477(7363):211-5
references: 21857683
references: Am J Pathol. 2008 Jul;173(1):182-94
references: 18535185
references: Brain Res. 2012 Jun 26;1462:61-80
references: 22445064
references: Trends Neurosci. 2011 Jul;34(7):339-48
references: 21700347
references: PLoS One. 2011;6(8):e23075
references: 21850253
references: Hum Mutat. 2009 Apr;30(4):688-94
references: 19224587
references: BMC Med Genet. 2010 Jan 19;11:8
references: 20082726
references: J Cell Sci. 2014 Jul 15;127(Pt 14):3024-38
references: 24860144
references: FASEB J. 2011 Jul;25(7):2344-53
references: 21450909
references: Neurobiol Dis. 2012 Mar;45(3):862-70
references: 22198567
references: J Biol Chem. 2010 Aug 20;285(34):26304-14
references: 20554523
references: Eur J Neurol. 2009 Jun;16(6):727-32
references: 19236453
references: Amyotroph Lateral Scler. 2010;11(1-2):223-7
references: 19714537
references: Neuron. 2014 Sep 3;83(5):1043-50
references: 25132468
references: Ann Neurol. 2013 Jul;74(1):20-38
references: 23686809
references: Curr Opin Cell Biol. 2010 Apr;22(2):192-8
references: 19962293
references: Nat Neurosci. 2014 May;17(5):664-666
references: 24686783
references: Seishin Shinkeigaku Zasshi. 1962 Jan 25;64:85-99
references: 14460927
references: Brain. 2014 Jul;137(Pt 7):2040-51
references: 24866055
references: Science. 2009 Feb 27;323(5918):1208-1211
references: 19251628
references: Hum Mol Genet. 2009 Oct 1;18(19):3725-38
references: 19567404
references: J Biol Chem. 2011 May 27;286(21):18845-55
references: 21454607
references: Hum Mol Genet. 2014 Feb 15;23(4):1025-35
references: 24105464
references: PLoS One. 2012;7(2):e31899
references: 22384095
references: J Biol Chem. 1999 Jul 9;274(28):19509-12
references: 10391881
references: Acta Neuropathol. 2013 Dec;126(6):859-79
references: 24096617
references: Ann Med. 2012 Dec;44(8):817-28
references: 22420316
references: FEBS Open Bio. 2013 Nov 20;4:1-10
references: 24319651
references: Mol Neurodegener. 2011 Aug 08;6:57
references: 21819629
references: Proc Natl Acad Sci U S A. 2014 Mar 25;111(12):E1121-9
references: 24616503
references: Amyotroph Lateral Scler. 2009 Aug;10(4):205-9
references: 19267274
references: Neuron. 2013 Aug 7;79(3):416-38
references: 23931993
references: J Biol Chem. 2005 Nov 11;280(45):37572-84
references: 16157593
references: Biochem Biophys Res Commun. 2006 Dec 22;351(3):602-11
references: 17084815
references: Lancet Neurol. 2012 Apr;11(4):323-30
references: 22406228
references: J Biomed Sci. 2013 May 30;20:33
references: 23721326
references: J Virol. 1995 Jun;69(6):3584-96
references: 7745706
references: Int J Cell Biol. 2012;2012:736905
references: 22518139
references: Proc Natl Acad Sci U S A. 2012 Sep 11;109(37):15024-9
references: 22932872
references: PLoS One. 2011;6(7):e22850
references: 21829535
references: J Neurosci Res. 2010 Mar;88(4):784-97
references: 19798749
references: Neuron. 2014 Feb 5;81(3):536-543
references: 24507191
references: Nat Genet. 2008 May;40(5):572-4
references: 18372902
references: Neurobiol Aging. 2015 Mar;36(3):1602.e17-27
references: 25499087
references: Science. 2014 Sep 5;345(6201):1139-45
references: 25081482
references: Genesis. 2010 Jan;48(1):56-62
references: 20014337
references: Cell Rep. 2013 Dec 12;5(5):1178-86
references: 24290757
references: Autophagy. 2010 Feb;6(2):217-27
references: 20104022
references: Acta Neuropathol. 2011 Dec;122(6):691-702
references: 22101323
references: J Biol Chem. 2012 Jun 29;287(27):23079-94
references: 22563080
references: J Neurosci. 2007 Sep 26;27(39):10530-4
references: 17898224
references: J Neurochem. 2011 Jan;116(2):248-59
references: 21062285
references: Proc Natl Acad Sci U S A. 2010 Feb 23;107(8):3858-63
references: 20133711
references: Acta Neuropathol. 2011 May;121(5):611-22
references: 21120508
references: Mol Cell. 2000 Aug;6(2):409-19
references: 10983987
references: Neurobiol Aging. 2012 Sep;33(9):2229.e11-2229.e18
references: 22575358
references: J Biol Chem. 2009 Oct 2;284(40):27416-24
references: 19651785
references: Biochem Biophys Res Commun. 2009 May 1;382(2):405-9
references: 19285963
references: Science. 2008 Mar 21;319(5870):1668-72
references: 18309045
references: Nat Genet. 2014 Feb;46(2):152-60
references: 24336168
references: Neuron. 2013 Oct 16;80(2):415-28
references: 24139042
references: J Neurol Neurosurg Psychiatry. 2009 Mar;80(3):354-5
references: 19228676
references: Neuron. 2011 Oct 20;72(2):245-56
references: 21944778
references: Acta Neuropathol. 2007 May;113(5):535-42
references: 17333220
references: Nat Genet. 2004 Apr;36(4):377-81
references: 15034582
references: EMBO J. 2011 Jan 19;30(2):277-88
references: 21131904
references: PLoS One. 2010 Dec 31;5(12):e15878
references: 21209826
references: Science. 2011 Jul 8;333(6039):228-33
references: 21617041
references: Proc Natl Acad Sci U S A. 2013 Nov 19;110(47):E4530-9
references: 24170860
references: Neuron. 2010 Dec 9;68(5):857-64
references: 21145000
references: PLoS One. 2014 Mar 20;9(3):e91269
references: 24651281
references: J Med Chem. 2014 Mar 27;57(6):2755-72
references: 24592867
references: Nat Neurosci. 2011 Apr;14(4):452-8
references: 21358640
references: Nat Chem Biol. 2014 Aug;10(8):677-85
references: 24974230
references: J Neurochem. 2009 Aug;110(3):1082-94
references: 19522733
references: Proc Natl Acad Sci U S A. 2010 Feb 16;107(7):3169-74
references: 20133767
references: Brain. 2013 May;136(Pt 5):1371-82
references: 23449777
references: Nat Neurosci. 2011 Apr;14(4):459-68
references: 21358643
references: Nature. 2010 Sep 9;467(7312):179-84
references: 20829789
references: Proc Natl Acad Sci U S A. 2013 Feb 19;110(8):E736-45
references: 23382207
references: Ann Neurol. 2008 Apr;63(4):538-42
references: 18438952
references: J Neurochem. 2009 Nov;111(4):1051-61
references: 19765185
references: Trends Cell Biol. 2000 Dec;10(12):524-30
references: 11121744
references: Sci Aging Knowledge Environ. 2003 Aug 27;2003(34):RE6
references: 12944592
references: J Cell Biol. 2009 Dec 14;187(6):875-88
references: 20008565
references: J Biol Chem. 2014 Feb 21;289(8):4653-9
references: 24371143
references: Biochim Biophys Acta. 2011 Dec;1812(12):1577-83
references: 21946215
references: Hum Mol Genet. 2014 Sep 15;23(18):4960-9
references: 24847002
references: Arch Neurol. 2011 Nov;68(11):1440-6
references: 22084127
references: PLoS One. 2014 Mar 04;9(3):e90452
references: 24595055
references: Neurobiol Aging. 2014 May;35(5):1212.e1-5
references: 24300238
references: Brain. 2013 May;136(Pt 5):1345-60
references: 23474849
references: J Biol Chem. 2007 Aug 17;282(33):24131-45
references: 17580304
references: Nature. 1981 Sep 24;293(5830):311-4
references: 6792546
references: Hum Mol Genet. 2011 Apr 1;20(7):1400-10
references: 21257637
references: Neuron. 2013 Feb 20;77(4):639-46
references: 23415312
references: J Hum Genet. 2010 Apr;55(4):252-4
references: 20224596
references: J Cell Sci. 2014 Mar 15;127(Pt 6):1263-78
references: 24424030
references: J Biol Chem. 2011 Apr 15;286(15):13171-83
references: 21339291
references: Neuropathology. 2012 Oct;32(5):505-14
references: 22181065
references: Autophagy. 2010 Oct;6(7):958-60
references: 20699640
references: Acta Neuropathol. 2013 Dec;126(6):845-57
references: 24170096
references: PLoS One. 2010 Oct 11;5(10):e13250
references: 20948999
references: Neurosci Lett. 2010 Jan 18;469(1):112-6
references: 19944744
references: Hum Mol Genet. 2010 Aug 15;19(16):3206-18
references: 20530643
references: Acta Neuropathol. 2012 Jun;123(6):825-39
references: 22426854
references: Exp Cell Res. 2013 Aug 1;319(13):1998-2005
references: 23742895
references: Cell. 2014 Jan 16;156(1-2):170-82
references: 24439375
references: EMBO J. 2010 Aug 18;29(16):2841-57
references: 20606625
references: Acta Neuropathol. 2007 Jul;114(1):63-70
references: 17492294
references: Hum Mol Genet. 2014 Jan 1;23(1):157-70
references: 23962724
references: J Neurol Neurosurg Psychiatry. 2009 Nov;80(11):1283-5
references: 19864663
references: Acta Neuropathol. 2010 Mar;119(3):355-64
references: 19967541
references: J Neuroinflammation. 2014 Jun 11;11:104
references: 24920309
references: EMBO Rep. 2009 Feb;10(2):173-9
references: 19148225
references: Proc Natl Acad Sci U S A. 2012 Apr 10;109(15):5803-8
references: 22451909
references: Science. 2014 Sep 5;345(6201):1192-1194
references: 25103406
references: J Clin Invest. 2011 Feb;121(2):726-38
references: 21206091
references: Arch Neurol. 2008 Sep;65(9):1185-9
references: 18779421
references: J Biol Chem. 2014 Jul 4;289(27):19164-79
references: 24825905
references: Nat Neurosci. 2012 Nov;15(11):1488-97
references: 23023293
references: Acta Neuropathol Commun. 2014 Jun 20;2:70
references: 24950788
references: J Biol Chem. 2012 Aug 10;287(33):27335-44
references: 22718760
references: Cell. 1993 Jun 18;73(6):1055-8
references: 8513491
references: EMBO Mol Med. 2013 Feb;5(2):221-34
references: 23255347
references: Mol Neurodegener. 2012 Jun 14;7:27
references: 22697423
references: Proc Natl Acad Sci U S A. 2010 Jul 27;107(30):13318-23
references: 20624952
references: Hum Mol Genet. 2013 Oct 1;22(19):3883-93
references: 23727833
references: PLoS Genet. 2010 Mar 26;6(3):e1000887
references: 20361056
references: Brain Res. 2012 Jun 26;1462:139-50
references: 22406069
references: Nature. 2013 Mar 28;495(7442):467-73
references: 23455423
references: Mol Cell Biol. 2004 Sep;24(18):8055-68
references: 15340068
references: Amyotroph Lateral Scler. 2008 Aug;9(4):195-211
references: 18608090
references: J Cell Sci. 2004 Jan 15;117(Pt 2):281-92
references: 14657277
references: Hum Mol Genet. 2015 Mar 15;24(6):1630-45
references: 25398948
references: Nat Neurosci. 2014 Jan;17(1):17-23
references: 24369373
references: Neurogenetics. 2010 May;11(2):217-25
references: 19760257
references: J Biol Chem. 2013 Feb 1;288(5):3641-54
references: 23235148
references: J Biol Chem. 2009 Jul 24;284(30):20329-39
references: 19465477
references: PLoS One. 2010 Aug 18;5(8):e12247
references: 20806063
references: Hum Mol Genet. 2009 Sep 15;18(18):3353-64
references: 19515851
references: Nature. 2010 May 13;465(7295):223-6
references: 20428114
references: Acta Neuropathol. 2014 Oct;128(4):485-503
references: 25120191
references: Science. 2013 Mar 15;339(6125):1335-8
references: 23393093
references: J Biol Chem. 2014 Mar 7;289(10):6669-80
references: 24425868
references: Nature. 2004 Nov 11;432(7014):235-40
references: 15531877
references: Neuron. 2014 Oct 22;84(2):324-31
references: 25374358
references: Proc Natl Acad Sci U S A. 2013 Mar 19;110(12):4697-702
references: 23401527
references: J Biol Chem. 2010 Feb 26;285(9):6826-34
references: 20040602
references: Lancet Neurol. 2008 May;7(5):409-16
references: 18396105
references: Ann Neurol. 2007 May;61(5):427-34
references: 17469116
references: Acta Neuropathol Commun. 2013 Oct 14;1:68
references: 24252525
references: FEBS Lett. 2008 Aug 20;582(19):2899-904
references: 18656473
references: J Biol Chem. 2013 Feb 8;288(6):4103-15
references: 23258539
references: Hum Mol Genet. 2010 Feb 15;19(4):671-83
references: 19959528
references: Arch Neurol. 2012 Sep;69(9):1154-8
references: 22637429
references: Lancet Neurol. 2013 May;12(5):435-42
references: 23541756
references: J Biol Chem. 2008 May 9;283(19):13302-9
references: 18305110
references: PLoS Genet. 2008 Sep 19;4(9):e1000193
references: 18802454
references: Mol Cell Biol. 2011 Mar;31(5):1098-108
references: 21173160
references: Hum Mutat. 2012 Sep;33(9):1345-51
references: 22753137
references: Science. 2006 Oct 6;314(5796):130-3
references: 17023659
references: Neuropathology. 2009 Dec;29(6):672-83
references: 19496940
references: Proc Natl Acad Sci U S A. 2009 May 5;106(18):7607-12
references: 19383787
references: Mol Cell Proteomics. 2010 Apr;9(4):705-18
references: 20047951
references: J Med Genet. 2009 Feb;46(2):112-4
references: 18931000
references: Acta Neuropathol. 2010 Apr;119(4):409-19
references: 20198480
references: Nat Chem Biol. 2006 Jun;2(6):319-23
references: 16699519
references: Acta Neuropathol. 2009 Feb;117(2):137-49
references: 19125255