title: Stress granules as crucibles of ALS pathogenesis.
abstract: Amyotrophic lateral sclerosis (ALS) is a fatal human neurodegenerative disease affecting primarily motor neurons. Two RNA-binding proteins, TDP-43 and FUS, aggregate in the degenerating motor neurons of ALS patients, and mutations in the genes encoding these proteins cause some forms of ALS. TDP-43 and FUS and several related RNA-binding proteins harbor aggregation-promoting prion-like domains that allow them to rapidly self-associate. This property is critical for the formation and dynamics of cellular ribonucleoprotein granules, the crucibles of RNA metabolism and homeostasis. Recent work connecting TDP-43 and FUS to stress granules has suggested how this cellular pathway, which involves protein aggregation as part of its normal function, might be coopted during disease pathogenesis.
authors: Medical Scientist Training Program and, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Yun R
authors: YR
authors: Li
authors: Oliver D
authors: OD
authors: King
authors: James
authors: J
authors: Shorter
authors: Aaron D
authors: AD
authors: Gitler
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D000067528:Ataxins; D003594:Cytoplasmic Granules / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D004781:Environmental Exposure; D006801:Humans; D009419:Nerve Tissue Proteins / Q000378:metabolism; D011328:Prions / Q000378:metabolism; D017434:Protein Structure, Tertiary; D034702:RNA-Binding Protein FUS / Q000378:metabolism; D013312:Stress, Physiological
chemical_list: D000067528:Ataxins; D004268:DNA-Binding Proteins; D009419:Nerve Tissue Proteins; D011328:Prions; D034702:RNA-Binding Protein FUS
references: Genes Dev. 2012 Dec 15;26(24):2690-5
references: 23249733
references: Science. 2009 Feb 27;323(5918):1208-1211
references: 19251628
references: Nucleic Acids Res. 2005 Oct 27;33(18):6000-10
references: 16254078
references: Mol Biosyst. 2010 Jul;6(7):1115-30
references: 20422111
references: Nat Genet. 2000 Feb;24(2):175-9
references: 10655065
references: Curr Opin Neurobiol. 2011 Dec;21(6):904-19
references: 21813273
references: Proc Natl Acad Sci U S A. 2011 Dec 27;108(52):20881-90
references: 22065782
references: Mol Neurodegener. 2012 Oct 24;7:54
references: 23092511
references: Nature. 2012 Mar 07;483(7389):336-40
references: 22398450
references: Nat Med. 2004 Oct;10(10):1055-63
references: 15459709
references: Nat Rev Genet. 2005 Jun;6(6):435-50
references: 15931169
references: J Biol Chem. 2009 Dec 25;284(52):36569-36580
references: 19843517
references: Brain Res. 2012 Jun 26;1462:61-80
references: 22445064
references: Prion. 2011 Jul-Sep;5(3):179-87
references: 21847013
references: Mol Cell. 2009 Dec 25;36(6):932-41
references: 20064460
references: Proc Natl Acad Sci U S A. 2012 Jul 24;109(30):12017-21
references: 22778397
references: Nucleic Acids Res. 2012 Mar;40(6):2668-82
references: 22121224
references: Biochim Biophys Acta. 2013 May;1834(5):918-31
references: 23328411
references: Mol Neurodegener. 2012 Nov 20;7:56
references: 23164372
references: J Cell Sci. 2011 Jan 15;124(Pt 2):228-39
references: 21172806
references: J Biol Chem. 2012 May 4;287(19):15635-47
references: 22427648
references: Biochem Biophys Res Commun. 2006 Dec 22;351(3):602-11
references: 17084815
references: J Cell Sci. 2010 Apr 15;123(Pt 8):1191-201
references: 20356930
references: J Virol. 1995 Jun;69(6):3584-96
references: 7745706
references: Nature. 2007 May 24;447(7143):453-7
references: 17468747
references: Neurology. 2009 Sep 8;73(10):805-11
references: 19738176
references: Brain Res. 2012 Jun 26;1462:16-25
references: 22405725
references: Science. 2008 Dec 12;322(5908):1713-7
references: 18948503
references: Proc Natl Acad Sci U S A. 2008 Mar 11;105(10):3785-9
references: 18305152
references: Annu Rev Neurosci. 2007;30:575-621
references: 17417937
references: Neurochem Int. 2012 Mar;60(4):415-24
references: 22306778
references: Mol Cell Biol. 2006 Aug;26(15):5744-58
references: 16847328
references: J Biol Chem. 2012 Jun 29;287(27):23079-94
references: 22563080
references: Hum Mol Genet. 2013 Mar 15;22(6):1193-205
references: 23257289
references: J Proteome Res. 2012 May 4;11(5):2721-38
references: 22416763
references: Science. 2000 Jan 28;287(5453):661-4
references: 10650001
references: J Cell Sci. 2008 Aug 1;121(Pt 15):2463-72
references: 18611963
references: Cold Spring Harb Symp Quant Biol. 2011;76:91-9
references: 22371371
references: Biol Cell. 2008 Jan;100(1):27-38
references: 18072942
references: Mol Biol Cell. 2004 Dec;15(12):5383-98
references: 15371533
references: Mol Cell. 2007 Mar 9;25(5):635-46
references: 17349952
references: Acta Neuropathol. 2013 Mar;125(3):413-23
references: 23381195
references: Science. 2009 Jun 26;324(5935):1729-32
references: 19460965
references: Cell Rep. 2012 Oct 25;2(4):799-806
references: 23022481
references: Curr Biol. 2000 May 4;10(9):R335-7
references: 10801430
references: PLoS One. 2012;7(11):e50134
references: 23209657
references: J Neural Transm (Vienna). 2003 May;110(5):517-36
references: 12721813
references: Genetics. 2013 Jan;193(1):109-23
references: 23105015
references: J Biol Chem. 2003 Feb 7;278(6):3572-9
references: 12458215
references: Nat Neurosci. 2011 Apr;14(4):459-68
references: 21358643
references: J Biol Chem. 2005 Feb 11;280(6):4144-53
references: 15525641
references: Biochim Biophys Acta. 2010 Jul;1803(7):865-71
references: 20362631
references: J Neurosci. 2012 Jul 4;32(27):9133-42
references: 22764223
references: J Cell Sci. 2008 Nov 15;121(Pt 22):3778-85
references: 18957508
references: Proc Natl Acad Sci U S A. 2013 Feb 19;110(8):E736-45
references: 23382207
references: Cell. 1998 Jul 10;94(1):73-82
references: 9674429
references: J Neurochem. 2009 Nov;111(4):1051-61
references: 19765185
references: EMBO J. 2001 Apr 2;20(7):1774-84
references: 11285240
references: Cell. 2012 May 11;149(4):753-67
references: 22579281
references: Nat Cell Biol. 2011 Feb;13(2):167-73
references: 21240286
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: PLoS One. 2012;7(6):e38658
references: 22761693
references: Cell. 2009 Apr 3;137(1):146-58
references: 19345193
references: Nat Rev Neurosci. 2001 Nov;2(11):806-19
references: 11715057
references: Hum Mol Genet. 2010 Apr 15;19(R1):R46-64
references: 20400460
references: Cold Spring Harb Perspect Biol. 2011 Jan 01;3(1):a006833
references: 21421910
references: PLoS One. 2010 Oct 11;5(10):e13250
references: 20948999
references: Neurobiol Aging. 2011 Dec;32(12):2323.e27-40
references: 20674093
references: Cell. 2012 May 11;149(4):768-79
references: 22579282
references: EMBO J. 2010 Aug 18;29(16):2841-57
references: 20606625
references: Acta Neuropathol. 2007 Jul;114(1):63-70
references: 17492294
references: Brain. 2011 Sep;134(Pt 9):2595-609
references: 21856723
references: Adv Exp Med Biol. 2013;768:23-43
references: 23224963
references: Cell. 2012 Jun 8;149(6):1188-91
references: 22682242
references: Nature. 2010 Aug 26;466(7310):1069-75
references: 20740007
references: Nat Neurosci. 2012 Nov;15(11):1488-97
references: 23023293
references: J Neurosci. 2012 Jun 13;32(24):8270-83
references: 22699908
references: Hum Mutat. 2013 Apr;34(4):572-7
references: 23348830
references: Mol Cell Biol. 2010 Jan;30(1):186-96
references: 19841068
references: Science. 2004 Jun 18;304(5678):1793-7
references: 15155912
references: J Cell Biol. 2005 Jun 20;169(6):871-84
references: 15967811
references: J Biol Chem. 2005 Jun 24;280(25):23869-75
references: 15845535
references: EMBO Mol Med. 2013 Feb;5(2):221-34
references: 23255347
references: PLoS Biol. 2011 Apr;9(4):e1000614
references: 21541367
references: Acta Neuropathol. 2011 Jul;122(1):111-3
references: 21644037
references: Nature. 2013 Mar 28;495(7442):467-73
references: 23455423
references: Trends Biochem Sci. 2008 Mar;33(3):141-50
references: 18291657
references: J Biol Chem. 2009 Jul 24;284(30):20329-39
references: 19465477
references: Nat Rev Neurosci. 2010 Mar;11(3):155-9
references: 20029438
references: PLoS One. 2010 Aug 18;5(8):e12247
references: 20806063
references: Hum Mol Genet. 2010 Nov 1;19(21):4160-75
references: 20699327
references: Genes Dev. 2007 Dec 15;21(24):3381-94
references: 18079183
references: Curr Biol. 2005 Mar 29;15(6):587-93
references: 15797031
references: Science. 2012 Aug 31;337(6098):1047-9
references: 22936764
references: Neuron. 2009 Dec 24;64(6):783-90
references: 20064386
references: Mol Cell Biol. 2011 Mar;31(5):1098-108
references: 21173160
references: Science. 2006 Oct 6;314(5796):130-3
references: 17023659
references: Hum Mol Genet. 2012 Jul 1;21(13):2899-911
references: 22454397
references: Nat Genet. 2012 Dec;44(12):1302-9
references: 23104007