Chronic oxidative damage together with genome repair deficiency in the neurons is a double whammy for neurodegeneration: Is damage response signaling a potential therapeutic target?
A foremost challenge for the neurons, which are among the most oxygenated cells, is the genome damage caused by chronic exposure to endogenous reactive oxygen species (ROS), formed as cellular respiratory byproducts. Strong metabolic activity associated with high transcriptional levels in these long lived post-mitotic cells render them vulnerable to oxidative genome damage, including DNA strand breaks and mutagenic base lesions. There is growing evidence for the accumulation of unrepaired DNA lesions in the central nervous system (CNS) during accelerated aging and progressive neurodegeneration. Several germ line mutations in DNA repair or DNA damage response (DDR) signaling genes are uniquely manifested in the phenotype of neuronal dysfunction and are etiologically linked to many neurodegenerative disorders. Studies in our lab and elsewhere revealed that pro-oxidant metals, ROS and misfolded amyloidogenic proteins not only contribute to genome damage in CNS, but also impede their repair/DDR signaling leading to persistent damage accumulation, a common feature in sporadic neurodegeneration. Here, we have reviewed recent advances in our understanding of the etiological implications of DNA damage vs. repair imbalance, abnormal DDR signaling in triggering neurodegeneration and potential of DDR as a target for the amelioration of neurodegenerative diseases.
Department of Radiation Oncology, Houston Methodist Research Institute, Houston, TX 77030, USA; Houston Methodist Neurological Institute, Houston, TX 77030, USA.
Haibo
H
Wang
Department of Radiation Oncology, Houston Methodist Research Institute, Houston, TX 77030, USA; Houston Methodist Neurological Institute, Houston, TX 77030, USA.
Prakash
P
Dharmalingam
Department of Radiation Oncology, Houston Methodist Research Institute, Houston, TX 77030, USA; Centre for Neuroscience, Instituto de Investigaciones Científicas y Servicios de Alta Tecnología (INDICASAT AIP), City of Knowledge, Panama City, Panama; Department of Biotechnology, Acharya Nagarjuna University, Guntur, AP, India; Houston Methodist Neurological Institute, Houston, TX 77030, USA.
Velmarini
V
Vasquez
Department of Radiation Oncology, Houston Methodist Research Institute, Houston, TX 77030, USA; Houston Methodist Neurological Institute, Houston, TX 77030, USA.
Joy
J
Mitra
Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA.
Istvan
I
Boldogh
Centre for Neuroscience, Instituto de Investigaciones Científicas y Servicios de Alta Tecnología (INDICASAT AIP), City of Knowledge, Panama City, Panama.
K S
KS
Rao
Department of Neurology, Baylor College of Medicine and Center for Translational Research on Inflammatory Diseases Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX 77030, USA.
Thomas A
TA
Kent
Department of Radiation Oncology, Houston Methodist Research Institute, Houston, TX 77030, USA; Weill Medical College of Cornell University, New York, USA.
Sankar
S
Mitra
Department of Radiation Oncology, Houston Methodist Research Institute, Houston, TX 77030, USA; Houston Methodist Neurological Institute, Houston, TX 77030, USA; Weill Medical College of Cornell University, New York, USA. Electronic address: mlhegde@houstonmethodist.org.
Muralidhar L
ML
Hegde
D000818:Animals; D053903:DNA Breaks, Double-Stranded; D015894:Genome, Human; D006801:Humans; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism*; D010084:Oxidation-Reduction; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction
D017382:Reactive Oxygen Species
DNA damage; DNA damage response; DNA repair defects; Neurodegeneration
Neurobiol Aging. 2004 Jan;25(1):71-81
14675733
Science. 1993 Aug 20;261(5124):1047-51
8351519
Cold Spring Harb Perspect Biol. 2013 Apr 01;5(4):a012583
23545420
Biochem Biophys Res Commun. 1997 Dec 18;241(2):221-5
9425253
J Biol Chem. 2000 Aug 18;275(33):25358-64
10851232
Stem Cell Res. 2013 Nov;11(3):1264-71
24041806
Biochemistry. 2003 Aug 19;42(32):9761-70
12911319
J Biol Chem. 2003 Dec 12;278(50):49679-84
14522990
Genes Dev. 2001 Sep 1;15(17):2177-96
11544175
Free Radic Res. 2014 Jul;48(7):794-805
24678962
DNA Repair (Amst). 2009 Jan 1;8(1):126-36
18935984
J Biol Chem. 2007 Mar 30;282(13):9469-74
17276982
FEBS J. 2009 Jan;276(1):27-35
19087197
DNA Repair (Amst). 2004 Aug-Sep;3(8-9):1207-17
15279809
J Neurochem. 2000 Feb;74(2):647-58
10646516
Nucleic Acids Res. 2007;35(16):5545-55
17704129
Mol Cell. 2009 Feb 13;33(3):344-53
19217408
DNA Repair (Amst). 2008 Jul 1;7(7):1110-20
18463003
Proc Natl Acad Sci U S A. 2006 Jun 27;103(26):10017-22
16777961
Neurogenetics. 2011 Aug;12(3):193-201
21465257
Parkinsonism Relat Disord. 2014 Jan;20 Suppl 1:S85-7
24262196
Lab Invest. 2000 Aug;80(8):1323-35
10950123
Cell Commun Signal. 2010 Dec 22;8:31
21176168
Neuroscience. 2007 Apr 14;145(4):1260-6
17045754
Nucleic Acids Res. 2010 Aug;38(15):5023-35
20385586
DNA Repair (Amst). 2015 Nov;35:90-105
26519823
Free Radic Biol Med. 2002 May 1;32(9):804-12
11978482
Cell Cycle. 2011 Jul 15;10 (14 ):2269-75
21636980
Nucleic Acids Res. 2015 Feb 27;43(4):2271-81
25662216
J Alzheimers Dis. 2011;24 Suppl 2:183-98
21441656
Glia. 2003 Jun;42(4):370-8
12730957
Iran Biomed J. 2012;16(4):223-5
23183622
Neurosci Lett. 2006 Jan 23;393(1):18-22
16226837
Curr Neuropharmacol. 2009 Mar;7(1):65-74
19721819
Nat Commun. 2015 Nov 30;6:8897
26615780
Neurobiol Aging. 2017 Jan;49:214.e1-214.e5
27480424
Nat Genet. 2010 Mar;42(3):245-9
20118933
Ann Neurol. 1984 Apr;15(4):329-34
6742779
Cell. 1999 Dec 10;99(6):577-87
10612394
Nat Clin Pract Neurol. 2007 Mar;3(3):162-72
17342192
Arch Biochem Biophys. 2007 Aug 1;464(1):57-69
17537399
Proc Natl Acad Sci U S A. 2012 Sep 11;109(37):14948-53
22927410
Int J Mol Sci. 2014 Dec 24;16(1):193-217
25547488
Cell Mol Life Sci. 2010 Nov;67(21):3573-87
20714778
Biochim Biophys Acta. 2014 Aug;1842(8):1198-207
24252612
DNA Repair (Amst). 2004 Aug-Sep;3(8-9):1227-35
15279811
PLoS Genet. 2015 Jan 29;11(1):e1004749
25633985
Nat Rev Neurosci. 2015 Feb;16(2):109-20
25588378
Genes Dev. 2001 Jul 15;15(14):1833-44
11459832
Biochemistry (Mosc). 2009 Nov;74(11):1253-9
19916941
Hum Mutat. 1999;14(1):9-22
10447254
Hum Mol Genet. 2009 Nov 1;18(21):4102-17
19643912
Proc Natl Acad Sci U S A. 2014 Oct 28;111(43):15550-5
25313065
Glia. 1998 Nov;24(3):304-12
9775981
Neurology. 1999 Nov 10;53(8):1787-93
10563629
J Neurochem. 2005 May;93(4):953-62
15857398
J Clin Invest. 2014 Jul;124(7):3137-46
24911150
Annu Rev Genet. 2005;39:359-407
16285865
Antioxid Redox Signal. 2006 Nov-Dec;8(11-12):2039-45
17034348
Proc Natl Acad Sci U S A. 2004 Jul 20;101(29):10726-31
15247418
Arch Biochem Biophys. 2006 May 15;449(1-2):143-56
16600170
Nature. 2011 Aug 21;477(7363):211-5
21857683
Brain Res Rev. 2008 Jun;58(1):136-48
18342372
Ann Neurol. 1993 Oct;34(4):609-16
8215249
J Neurochem. 2002 Jun;81(6):1273-84
12068075
J Neurol Sci. 2007 Sep 15;260(1-2):219-24
17572444
Nat Cell Biol. 2009 Feb;11(2):211-8
19151707
Hum Mutat. 1997;9(4):322-31
9101292
Arch Biochem Biophys. 2007 Jul 15;463(2):245-52
17502108
J Biol Chem. 2012 Jan 20;287(4):2618-31
22139836
J Neurosci. 2006 Jan 4;26(1):41-50
16399671
J Cereb Blood Flow Metab. 2006 Feb;26(2):181-98
16001017
Free Radic Biol Med. 2008 Sep 1;45(5):592-601
18515104
Hum Mol Genet. 2007 Jul 1;16(13):1604-18
17504823
Toxicology. 2010 Dec 5;278(2):199-203
19857538
Cell. 2006 Jan 27;124(2):301-13
16439205
Stroke. 2007 Oct;38(10):2861-3
17761912
Free Radic Res. 2002 Dec;36(12):1307-13
12607822
Nat Neurosci. 2013 May;16(5):613-21
23525040
Nat Neurosci. 2013 Aug;16(8):1008-15
23852118
J Biol Chem. 2009 Aug 14;284(33):22059-66
19535326
EMBO J. 2008 Jan 23;27(2):336-49
18216876
Arch Virol. 1999;144(9):1751-63
10542024
Mol Nutr Food Res. 2011 Sep;55(9):1291-300
21714128
Biochem J. 2008 Oct 15;415(2):297-307
18620545
Am J Hum Genet. 2009 May;84(5):605-16
19409520
DNA Repair (Amst). 2010 Dec 10;9(12 ):1307-14
21030321
DNA Repair (Amst). 2006 Dec 9;5(12):1489-94
16935573
Nature. 1968 May 18;218(5142):652-6
5655953
Nat Rev Genet. 2012 Dec;13(12):878-90
23154810
J Neurosci. 2000 Sep 15;20(18):6920-6
10995836
BMC Neurosci. 2015 Oct 23;16:69
26499115
Annu Rev Genet. 2006;40:363-83
16895466
Nucleic Acids Res. 1996 Nov 15;24(22):4387-94
8948628
J Neurosci. 2006 Oct 25;26(43):10949-57
17065437
Ann Neurol. 1994 Nov;36(5):747-51
7979220
Free Radic Biol Med. 2012 Jul 1;53(1):51-9
22583700
J Mol Neurosci. 2004;22(1-2):19-31
14742907
J Trace Elem Med Biol. 2004;18(2):163-71
15646263
Nature. 1993 Mar 4;362(6415):59-62
8446170
Free Radic Biol Med. 2012 Oct 1;53(7):1478-88
22709585
J Neurosci. 2004 Oct 20;24(42):9232-9
15496657
EMBO J. 2007 Nov 14;26(22):4720-31
17914460
PLoS Genet. 2009 Dec;5(12):e1000749
19997493
Free Radic Biol Med. 2010 Jun 15;48(12 ):1570-6
20171275
Nature. 2011 Mar 10;471(7337):245-8
21390132
Science. 2006 Oct 6;314(5796):130-3
17023659
Gene. 2014 Apr 15;539(2):270-4
24534463
Cell. 1985 Feb;40(2):359-69
3838150
Int J Dev Neurosci. 2008 Nov;26(7):665-71
18768156
DNA Repair (Amst). 2013 Aug;12(8):620-36
23684800
J Neurosci Res. 2007 Nov 1;85(14):3079-88
17638302
J Neurosci. 2014 Jun 4;34(23):7802-13
24899704
J Alzheimers Dis. 2009;17(3):457-68
19363258
Curr Mol Med. 2006 Nov;6(7):739-48
17100600
Neurochem Res. 2012 May;37(5):991-5
22219134
Am J Pathol. 2003 Mar;162(3):823-35
12598317
Brain Pathol. 1996 Oct;6(4):493-506
8944319
Sci Rep. 2016 Feb 25;6:22086
26912170
J Cereb Blood Flow Metab. 2010 Nov;30(11):1793-803
20736956
Nat Genet. 1999 Dec;23(4):471-3
10581038
Nature. 2005 Mar 3;434(7029):108-13
15744309
Acta Biochim Biophys Sin (Shanghai). 2009 Mar;41(3):179-87
19280056
Nucleus. 2015;6(1):23-9
25587791
Cell Mol Neurobiol. 2014 May;34(4):603-9
24659023
PLoS One. 2011;6(11):e27408
22096569
Cell Tissue Res. 2001 Aug;305(2):217-28
11545259
PLoS Genet. 2011 Dec;7(12):e1002405
22174697
J Neurochem. 1998 Nov;71(5):2034-40
9798928
Exp Gerontol. 2010 Mar;45(3):208-16
20005284
Antioxid Redox Signal. 2011 May 15;14(10):2013-54
20649473
Nat Med. 1997 Aug;3(8):872-8
9256278
J Alzheimers Dis. 2013;33(4):1059-71
23160010
Neuroscience. 2007 Apr 14;145(4):1187-200
16934943
J Neurosci. 2007 Nov 14;27(46):12555-64
18003834
Neurotox Res. 2016 Aug;30(2):251-67
27126805
PLoS Genet. 2015 Jan 15;11(1):e1004834
25590633
Proc Natl Acad Sci U S A. 1988 Sep;85(17):6465-7
3413108
Genes Dev. 2011 Mar 1;25(5):409-33
21363960
Biochim Biophys Acta. 2011 Nov;1812(11):1359-70
21871956
Science. 2009 Feb 27;323(5918):1208-11
19251628
J Neurochem. 1999 Feb;72(2):771-6
9930752
Neuroscience. 2007 Apr 14;145(4):1249-59
17097236
Neurobiol Aging. 2012 Jun;33(6):1034-44
20965613
J Neurosci Res. 2007 Apr;85(5):919-34
17279544
Proc Natl Acad Sci U S A. 1997 Aug 19;94(17):9463-8
9256505
J Neurosci. 2011 Nov 30;31(48):17649-58
22131425
Exp Gerontol. 2010 Aug;45(7-8):478-88
20096766
Genet Test Mol Biomarkers. 2012 Jun;16(6):504-7
22224629
Free Radic Biol Med. 2009 Oct 1;47(7):1049-56
19616617
J Biol Chem. 2008 Feb 8;283(6):3130-40
18032376
J Alzheimers Dis. 2001 Aug;3(4):377-385
12214040
Environ Mol Mutagen. 2010 Jun;51(5):417-26
20544882
Mutat Res. 2002 Dec;512(2-3):135-53
12464348
Neurosci Lett. 2016 Jan 12;611:112-5
26628246
Hum Mol Genet. 2004 Oct 15;13(20):2369-76
15333585
Nucleic Acids Res. 2015 Jan;43(2):943-59
25552414
J Pharmacol Exp Ther. 2004 Jun;309(3):1067-78
14985416
Front Biosci (Landmark Ed). 2010 Jan 01;15:418-36
20036828
Hum Mol Genet. 2013 Dec 20;22(25):5146-59
23912341
Biol Trace Elem Res. 2014 Nov;161(2):151-60
25107328
J Neurochem. 1997 May;68(5):2061-9
9109533
Mol Cancer Res. 2004 Aug;2(8):433-41
15328370
Nat Genet. 2006 May;38(5):515-7
16604074
Front Genet. 2015 Jan 14;5:467
25642241
Stroke. 2009 May;40(5):e331-9
19182083
Mol Cell Biol. 1998 Jun;18(6):3563-71
9584196
Science. 1998 May 15;280(5366):1089-91
9582124
Mech Ageing Dev. 2011 Aug;132(8-9):443-8
21878349
Free Radic Biol Med. 2013 Oct;63:115-25
23684897
Mech Ageing Dev. 2017 Jan;161(Pt A):95-104
27233446
Free Radic Biol Med. 2008 Sep 15;45(6):813-9
18598755
J Cell Biol. 2010 May 3;189(3):425-43
20439996
Sci Transl Med. 2014 Dec 24;6(268):268ra178
25540325
J Neurosci. 1997 Feb 15;17(4):1397-405
9006981
Neuroreport. 1998 Dec 21;9(18):4015-8
9926839
PLoS Genet. 2008 Nov;4(11):e1000266
19023407
Mech Ageing Dev. 2017 Jan;161(Pt A):149-162
27364693
Mol Cancer Res. 2015 Mar;13(3):470-82
25563294
J Cereb Blood Flow Metab. 2011 Feb;31(2):680-92
20736962
Curr Biol. 2012 Sep 11;22(17):R753-61
22975006
Hum Mutat. 2009 Mar;30(3):438-45
19085937
PLoS One. 2016 Jan 29;11(1):e0147348
26824244
J Neurochem. 2010 Sep;114(6):1537-49
20557419
Biochim Biophys Acta. 2011 Jan;1813(1):186-200
20950654
Nat Genet. 2001 Oct;29(2):184-8
11586299
EMBO Rep. 2004 Aug;5(8):772-6
15289825
Front Neurol. 2013 May 15;4:53
23720649
Neuron. 2004 Feb 19;41(4):549-61
14980204
Nature. 2010 Aug 26;466(7310):1069-75
20740007
Biochem J. 2009 Feb 1;417(3):639-50
19133841
Exp Mol Med. 2015 Mar 13;47:e150
25766619
Acta Neurochir Suppl. 2011;111:123-8
21725742
Neurogenetics. 2013 Feb;14 (1):43-51
23224214
Sci Rep. 2016 May 09;6:25628
27156849
Genet Test Mol Biomarkers. 2016 Jan;20(1):11-7
26554302
Proc Natl Acad Sci U S A. 2007 Feb 27;104(9):3585-90
17360686
J Struct Biol. 2000 Jun;130(2-3):184-208
10940225
ScientificWorldJournal. 2011;11:1679-91
22125427
Am J Hum Genet. 1997 Feb;60(2):320-9
9012405
Arch Dermatol. 2009 Nov;145(11):1285-91
19917958
Nucleic Acids Res. 2000 Oct 15;28(20):3880-6
11024166
Nutrition. 2015 Feb;31(2):359-65
25592015
Nature. 2011 Mar 10;471(7337):240-4
21390131
Nat Genet. 2002 Oct;32(2):267-72
12244316
Neurobiol Aging. 2006 Apr;27(4):596-605
15908050
DNA Repair (Amst). 2004 Nov 2;3(11):1493-502
15380105
Free Radic Biol Med. 2000 Apr 15;28(8):1161-74
10889445
Nature. 1975 Dec 4;258(5534):427-9
1196376
Nat Neurosci. 2014 May;17(5):664-6
24686783
J Cereb Blood Flow Metab. 2003 Jun;23(6):629-52
12796711
Med Res Rev. 2009 Jul;29(4):547-70
19177468
Prog Mol Biol Transl Sci. 2012;110:123-53
22749145
Neuromolecular Med. 2006;8(4):495-511
17028372
Proc Natl Acad Sci U S A. 1994 Apr 12;91(8):3270-4
8159737
Mutat Res. 1998 Oct 21;409(1):17-29
9806499
Neurobiol Dis. 2014 Oct;70:214-23
24981012
J Exp Med. 2011 Nov 21;208(12):2429-47
22084410
Cell Res. 2008 Jan;18(1):27-47
18166975
Acta Neuropathol. 2009 Oct;118(4):541-52
19529948
Neurology. 2000 Feb 8;54(3):703-9
10680807
J Neurochem. 2009 Sep;110(6):1774-83
19619136
Am J Hum Genet. 2008 Mar;82(3):539-66
18319069
Nature. 2006 Oct 12;443(7112):713-6
16964241
Neuron. 2010 Dec 9;68(5):857-64
21145000
Antioxid Redox Signal. 2011 May 15;14(10):1905-18
20677909
Proc Natl Acad Sci U S A. 1990 Jun;87(12):4707-11
2352945
Neurosci Lett. 2007 Jun 13;420(2):163-8
17531381
J Neuropathol Exp Neurol. 2009 Feb;68(2):210-5
19151620
Ann Neurol. 2007 Feb;61(2):162-74
17315206
Biochem Biophys Res Commun. 2006 Dec 22;351(3):602-11
17084815
J Pharm Bioallied Sci. 2012 Apr;4(2):112-7
22557921
J Neurosci. 2011 Aug 31;31(35):12543-53
21880916
Nat Genet. 2001 Apr;27(4):417-21
11279524
J Biol Chem. 2010 Sep 10;285(37):28812-25
20622253
J Neurosci Res. 2007 May 15;85(7):1420-6
17348043
Mol Cell. 2002 May;9(5):1005-16
12049737
PLoS One. 2016 Mar 08;11(3):e0151026
26954031
FASEB J. 2003 Apr;17(6):668-74
12665480
Neurobiol Aging. 1990 May-Jun;11(3):169-73
2362649
Biochem Biophys Res Commun. 2002 Feb 8;290(5):1593-601
11820805
J Neurochem. 2001 Dec;79(6):1246-9
11752065
Nat Neurosci. 2009 Aug;12(8):973-80
19633665
Free Radic Biol Med. 2015 May;82:73-104
25640729
Nat Struct Mol Biol. 2012 Feb 12;19(3):276-82
22343725
J Neurosci. 1995 Dec;15(12):7837-46
8613723
Nucleic Acids Res. 2003 Oct 1;31(19):5526-33
14500814
Nature. 2010 May 13;465(7295):223-6
20428114
EMBO J. 2005 Jun 15;24(12):2224-33
15920477
Clin Cancer Res. 2008 Jul 1;14(13):4053-8
18593981
J Neurochem. 1999 Sep;73(3):1164-74
10461908
Nucleic Acids Res. 1999 Sep 15;27(18):3712-9
10471741
DNA Repair (Amst). 2009 Jun 4;8(6):760-6
19303373
Brain Res Mol Brain Res. 1998 Jun 1;57(1):63-72
9630519
Neuron Glia Biol. 2011 Feb;7(1):17-23
22032249
Toxicol Appl Pharmacol. 1991 Sep 15;110(3):477-85
1949015
Nat Genet. 2001 Oct;29(2):189-93
11586300
Brain Res Mol Brain Res. 2004 Sep 10;128(1):1-7
15337312
Cell. 1998 May 1;93(3):477-86
9590181
Am J Pathol. 1999 May;154(5):1423-9
10329595
Nature. 2012 Aug 23;488(7412):499-503
22801503
Brain Res Mol Brain Res. 2000 Dec 28;85(1-2):251-9
11146128
Curr Mol Med. 2015;15(2):119-28
25732151
Nat Rev Genet. 2008 Aug;9(8):619-31
18626472
PLoS One. 2013 Apr 23;8(4):e62277
23626796
Int J Mol Sci. 2016 Jun 01;17 (6):
27258260
Proc Natl Acad Sci U S A. 1993 Sep 1;90(17):7951-5
8367446
Science. 2009 Feb 27;323(5918):1205-8
19251627
Nat Rev Neurosci. 2009 Feb;10(2):100-12
19145234
Exp Neurol. 1999 Jul;158(1):206-13
10448433
Science. 1999 Oct 15;286(5439):552-5
10521354
Brain Res. 2001 Jun 29;905(1-2):250-3
11423103
DNA Repair (Amst). 2008 Jul 1;7(7):1010-27
18458000
J Biol Chem. 2000 Apr 21;275(16):11553-60
10766769
DNA Repair (Amst). 2007 May 1;6(5):649-57
17236820
Proc Natl Acad Sci U S A. 1996 Aug 20;93(17):8919-23
8799128
Nat Neurosci. 2013 Oct;16(10):1383-91
24036913
J Neurochem. 2002 Jan;80(1):111-8
11796749