title: Protein homeostasis and aging in neurodegeneration.
abstract: Genetic and environmental factors responsible for numerous neurodegenerative diseases vary between disorders, yet age remains a universal risk factor. Age-associated decline in protein homeostasis, or proteostasis, enables disease-linked proteins to adopt aberrant tertiary structures, accumulate as higher-ordered aggregates, and cause a myriad of cellular dysfunctions and neuronal death. However, recent findings suggest that the assembly of disease proteins into tightly ordered aggregates can significantly delay proteotoxic onset. Furthermore, manipulation of metabolic pathways through key signaling components extends lifespan, bolsters proteostasis networks, and delays the onset of proteotoxicity. Thus, understanding the relationship between proteostasis and aging has provided important insights into neurodegeneration.
authors.affiliation: Howard Hughes Medical Institute, Glenn Center for Aging Research, Molecular and Cell Biology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Douglas
authors.forename: Andrew
authors.initials: A
authors.lastname: Dillin
mesh_terms: D000375:Aging / Q000378:metabolism*; D000818:Animals; D002477:Cells / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D053858:Metabolic Networks and Pathways; D009410:Nerve Degeneration / Q000378:metabolism* / Q000503:physiopathology; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D011506:Proteins
references.citation: PLoS Genet. 2009 May;5(5):e1000486
references.pmid: 19461873
references.citation: Acta Neuropathol. 2007 Dec;114(6):551-71
references.pmid: 17805553
references.citation: Proc Natl Acad Sci U S A. 2004 Jul 20;101(29):10804-9
references.pmid: 15249677
references.citation: Science. 2009 Jul 10;325(5937):201-4
references.pmid: 19590001
references.citation: Proc Natl Acad Sci U S A. 2008 May 20;105(20):7206-11
references.pmid: 18480252
references.citation: Nature. 2010 Mar 25;464(7288):504-12
references.pmid: 20336132
references.citation: Nat Rev Genet. 2005 Jun;6(6):435-50
references.pmid: 15931169
references.citation: Science. 2005 Nov 18;310(5751):1193-6
references.pmid: 16293764
references.citation: JAMA. 2001 Feb 14;285(6):739-47
references.pmid: 11176911
references.citation: Science. 2005 Jul 15;309(5733):476-81
references.pmid: 16020737
references.citation: Curr Biol. 2004 May 25;14(10):885-90
references.pmid: 15186745
references.citation: Nature. 2009 Feb 5;457(7230):726-30
references.pmid: 19079239
references.citation: Proc Natl Acad Sci U S A. 2002 Aug 6;99(16):10417-22
references.pmid: 12122205
references.citation: Mol Biol Cell. 1992 Oct;3(10):1141-54
references.pmid: 1421571
references.citation: Curr Alzheimer Res. 2008 Apr;5(2):179-86
references.pmid: 18393803
references.citation: Lancet. 1990 Jul 7;336(8706):7-9
references.pmid: 1973256
references.citation: Nature. 2004 Sep 9;431(7005):184-7
references.pmid: 15311209
references.citation: Neurobiol Dis. 2000 Feb;7(1):9-22
references.pmid: 10671319
references.citation: Mol Cell. 2006 Sep 15;23(6):887-97
references.pmid: 16973440
references.citation: Science. 2003 Oct 31;302(5646):841
references.pmid: 14593171
references.citation: Proc Natl Acad Sci U S A. 1994 Jun 7;91(12):5562-6
references.pmid: 8202528
references.citation: Cell. 1998 Oct 2;95(1):55-66
references.pmid: 9778247
references.citation: Exp Neurol. 1997 Jan;143(1):82-102
references.pmid: 9000448
references.citation: Proc Natl Acad Sci U S A. 2004 Nov 9;101(45):15998-6003
references.pmid: 15520384
references.citation: Biochemistry. 2004 May 11;43(18):5539-50
references.pmid: 15122920
references.citation: Exp Gerontol. 2008 Dec;43(12):1086-93
references.pmid: 18799131
references.citation: J Neurosci. 2010 Apr 7;30(14):4845-56
references.pmid: 20371804
references.citation: Proc Natl Acad Sci U S A. 2002 Aug 6;99(16):10813-8
references.pmid: 12122208
references.citation: PLoS Biol. 2004 Sep;2(9):E296
references.pmid: 15328540
references.citation: Cell. 2009 Dec 11;139(6):1157-69
references.pmid: 20005808
references.citation: Clin Anat. 1995;8(6):429-31
references.pmid: 8713166
references.citation: Neurology. 1992 Mar;42(3 Pt 1):669-70
references.pmid: 1347910
references.citation: Nature. 2009 Jul 16;460(7253):392-5
references.pmid: 19587680
references.citation: Science. 1990 Jun 1;248(4959):1122-4
references.pmid: 2111583
references.citation: Science. 2009 Feb 20;323(5917):1063-6
references.pmid: 19229036
references.citation: J Biol Chem. 2006 Aug 4;281(31):21745-21754
references.pmid: 16751189
references.citation: Curr Biol. 2007 Oct 9;17(19):1646-56
references.pmid: 17900900
references.citation: PLoS Pathog. 2007 Aug 31;3(8):e125
references.pmid: 17784787
references.citation: Cell Metab. 2008 Aug;8(2):157-68
references.pmid: 18599363
references.citation: Science. 1998 Jan 9;279(5348):242-7
references.pmid: 9422699
references.citation: Neuron. 2001 Jan;29(1):15-32
references.pmid: 11182078
references.citation: J Alzheimers Dis. 2006 Dec;10(4):417-22
references.pmid: 17183154
references.citation: J Cell Biol. 1985 Oct;101(4):1371-8
references.pmid: 3930508
references.citation: Nature. 2005 Jun 9;435(7043):773-8
references.pmid: 15944695
references.citation: Science. 2009 May 29;324(5931):1196-8
references.pmid: 19372390
references.citation: FASEB J. 2009 Oct;23(10):3315-24
references.pmid: 19487308
references.citation: J Neurosci. 2000 Aug 15;20(16):6021-9
references.pmid: 10934251
references.citation: Nature. 2005 Sep 8;437(7056):257-61
references.pmid: 16148934
references.citation: Proc Natl Acad Sci U S A. 2010 Apr 27;107(17):7710-5
references.pmid: 20385841
references.citation: J Biol Chem. 1998 Feb 13;273(7):3963-6
references.pmid: 9461583
references.citation: Proc Natl Acad Sci U S A. 2000 Aug 15;97(17):9712-7
references.pmid: 10931940
references.citation: Proc Natl Acad Sci U S A. 2006 Mar 14;103(11):4246-51
references.pmid: 16537516
references.citation: Science. 2007 Jul 27;317(5837):516-9
references.pmid: 17588900
references.citation: Aging Cell. 2007 Feb;6(1):95-110
references.pmid: 17266679
references.citation: Lancet. 1997 Jul 12;350(9071):134-8
references.pmid: 9228977
references.citation: Nat Med. 2004 Jul;10 Suppl:S2-9
references.pmid: 15272266
references.citation: J Neurosci Res. 1999 Jul 15;57(2):195-206
references.pmid: 10398297
references.citation: Nat Med. 2008 Aug;14(8):837-42
references.pmid: 18568035
references.citation: Cell. 1989 Apr 7;57(1):115-26
references.pmid: 2649245
references.citation: Proc Natl Acad Sci U S A. 1998 Nov 10;95(23):13363-83
references.pmid: 9811807
references.citation: Proc Natl Acad Sci U S A. 2008 Mar 4;105(9):3374-9
references.pmid: 18296641
references.citation: Ageing Res Rev. 2011 Apr;10(2):225-37
references.pmid: 20385253
references.citation: FASEB J. 2005 Apr;19(6):659-61
references.pmid: 15650008
references.citation: Science. 2000 Sep 22;289(5487):2126-8
references.pmid: 11000115
references.citation: Nat Genet. 2006 Jan;38(1):11-2
references.pmid: 16380721
references.citation: Annu Rev Neurosci. 2003;26:267-98
references.pmid: 12704221
references.citation: Neuron. 2009 Aug 13;63(3):316-28
references.pmid: 19679072
references.citation: Nature. 2003 Jan 9;421(6919):182-7
references.pmid: 12483226
references.citation: PLoS Biol. 2006 Jan;4(1):e6
references.pmid: 16300414
references.citation: Nature. 2004 Oct 14;431(7010):805-10
references.pmid: 15483602
references.citation: Nat Rev Mol Cell Biol. 2007 Feb;8(2):101-12
references.pmid: 17245412
references.citation: Nature. 1993 Dec 2;366(6454):461-4
references.pmid: 8247153
references.citation: Nature. 2003 Dec 11;426(6967):620
references.pmid: 14668850
references.citation: Prion. 2009 Apr-Jun;3(2):51-8
references.pmid: 19421006
references.citation: Neuroscience. 2007 Jul 13;147(3):746-56
references.pmid: 17583434
references.citation: Science. 2008 Feb 15;319(5865):916-9
references.pmid: 18276881
references.citation: Neurobiol Aging. 1989 Jul-Aug;10(4):317-22
references.pmid: 2682315
references.citation: PLoS Genet. 2008 Mar 21;4(3):e1000027
references.pmid: 18369446
references.citation: Genes Dev. 2006 Nov 1;20(21):2913-21
references.pmid: 17079682
references.citation: Hear Res. 1990 Oct;48(3):275-9
references.pmid: 2272936
references.citation: Science. 2003 Jan 24;299(5606):572-4
references.pmid: 12543978
references.citation: Nature. 2006 Jun 15;441(7095):885-9
references.pmid: 16625204
references.citation: Science. 2001 Apr 6;292(5514):107-10
references.pmid: 11292875
references.citation: Mol Biol Cell. 2004 Feb;15(2):657-64
references.pmid: 14668486
references.citation: J Neurosci. 2007 Apr 4;27(14):3650-62
references.pmid: 17409229
references.citation: Hum Mol Genet. 2006 Feb 1;15(3):433-42
references.pmid: 16368705
references.citation: Annu Rev Neurosci. 2000;23:217-47
references.pmid: 10845064
references.citation: Nat Neurosci. 2009 Sep;12(9):1129-35
references.pmid: 19684592
references.citation: J Cell Biol. 2009 Sep 7;186(5):703-11
references.pmid: 19720874
references.citation: Science. 2006 Mar 10;311(5766):1471-4
references.pmid: 16469881
references.citation: Aging Cell. 2009 Dec;8(6):756-60
references.pmid: 19747233
references.citation: Arch Neurol. 2002 Aug;59(8):1258-63
references.pmid: 12164721
references.citation: Proc Natl Acad Sci U S A. 2009 Sep 1;106(35):14914-9
references.pmid: 19706382
references.citation: Genes Dev. 1999 Oct 1;13(19):2570-80
references.pmid: 10521401
references.citation: Biochem Biophys Res Commun. 1984 May 16;120(3):885-90
references.pmid: 6375662
references.citation: J Am Geriatr Soc. 1966 May;14(5):431-46
references.pmid: 9752380
references.citation: Hum Mol Genet. 2008 Dec 1;17(23):3767-75
references.pmid: 18762557
references.citation: Nature. 2006 Nov 16;444(7117):337-42
references.pmid: 17086191
references.citation: Science. 2006 Sep 15;313(5793):1604-10
references.pmid: 16902091
references.citation: Nat Genet. 2004 Jun;36(6):585-95
references.pmid: 15146184
references.citation: J Biol Chem. 2007 Aug 17;282(33):23818-28
references.pmid: 17548355
references.citation: Mech Ageing Dev. 2004 Jun;125(6):397-403
references.pmid: 15272501
references.citation: Ann Intern Med. 2004 Apr 20;140(8):627-38
references.pmid: 15096334
references.citation: Nat Rev Neurosci. 2002 Apr;3(4):281-90
references.pmid: 11967558
references.citation: Proc Natl Acad Sci U S A. 1999 Mar 16;96(6):3228-33
references.pmid: 10077666
references.citation: Nat Rev Genet. 2007 Nov;8(11):835-44
references.pmid: 17909538
references.citation: Hum Mol Genet. 2002 May 1;11(9):1107-17
references.pmid: 11978769
references.citation: Science. 2003 Apr 18;300(5618):486-9
references.pmid: 12702875
references.citation: Biochem Biophys Res Commun. 2005 Mar 4;328(1):292-305
references.pmid: 15670783
references.citation: Cell. 2006 Jun 16;125(6):1165-77
references.pmid: 16777605
references.citation: PLoS One. 2009;4(2):e4535
references.pmid: 19229346
references.citation: Genetics. 1987 May;116(1):9-22
references.pmid: 3297920
references.citation: Mech Ageing Dev. 2007 Oct;128(10):546-52
references.pmid: 17875315
references.citation: Nature. 2004 Aug 5;430(7000):686-9
references.pmid: 15254550
references.citation: Nature. 2007 May 31;447(7144):550-5
references.pmid: 17476212
references.citation: Neurology. 1992 Mar;42(3 Pt 1):631-9
references.pmid: 1549228
references.citation: Cell. 1993 Jul 2;73(7):1339-47
references.pmid: 8100741
references.citation: Neuron. 2002 Aug 29;35(5):819-22
references.pmid: 12372277
references.citation: Nat Med. 1996 Jul;2(7):783-7
references.pmid: 8673924
references.citation: Aging Cell. 2008 Jun;7(3):394-404
references.pmid: 18331616
references.citation: Proc Natl Acad Sci U S A. 2004 Apr 27;101(17):6403-8
references.pmid: 15084750
references.citation: J Neural Transm (Vienna). 2005 Jun;112(6):813-38
references.pmid: 15517432
references.citation: Nature. 2001 Mar 8;410(6825):227-30
references.pmid: 11242085
references.citation: Genes Dev. 2008 Jun 1;22(11):1427-38
references.pmid: 18519635
references.citation: Annu Rev Neurosci. 2005;28:57-87
references.pmid: 16022590
references.citation: Biochem Biophys Res Commun. 2009 Aug 14;386(1):257-62
references.pmid: 19523444
references.citation: Neuron. 2003 Sep 11;39(6):889-909
references.pmid: 12971891
references.citation: Nat Cell Biol. 2006 Oct;8(10):1163-70
references.pmid: 16980958
references.citation: Science. 2003 May 16;300(5622):1142-5
references.pmid: 12750521
references.citation: Science. 1997 Sep 26;277(5334):1990-3
references.pmid: 9302293
references.citation: Nature. 1999 Apr 8;398(6727):513-7
references.pmid: 10206644
references.citation: Arch Neurol. 2004 Mar;61(3):378-84
references.pmid: 15023815
references.citation: J Biol Chem. 2003 Jul 4;278(27):25009-13
references.pmid: 12719433
references.citation: Science. 1997 Jul 4;277(5322):99-101
references.pmid: 9204908
references.citation: Nat Med. 1999 May;5(5):560-4
references.pmid: 10229234
references.citation: Nature. 1963 Jan 12;197:192-3
references.pmid: 14032480
references.citation: Nat Rev Neurosci. 2005 Jan;6(1):11-22
references.pmid: 15611723
references.citation: Hum Mol Genet. 2002 Oct 1;11(20):2395-407
references.pmid: 12351575
references.citation: Nat Rev Mol Cell Biol. 2009 May;10(5):307-18
references.pmid: 19339977
references.citation: J Biol Chem. 2005 Nov 11;280(45):37377-82
references.pmid: 16162502
references.citation: Nat Genet. 2005 Apr;37(4):349-50
references.pmid: 15793589
references.citation: PLoS Genet. 2005 Nov;1(5):e69
references.pmid: 16311627
references.citation: Ann Neurol. 1999 Dec;46(6):842-9
references.pmid: 10589536
references.citation: Nature. 2000 Mar 23;404(6776):394-8
references.pmid: 10746727