Skip to main content

Advertisement

SpringerLink
Log in

Malfunctioning DNA Damage Response (DDR) Leads to the Degeneration of Nigro-Striatal Pathway in Mouse Brain

  • Published:
Journal of Molecular Neuroscience Aims and scope Submit manuscript

Abstract

Pronounced neuropathology is a feature of ataxia-telangiectasia (A-T) and Nijmegen breakage syndrome (NBS), which are both genomic instability syndromes. The Nbs1 protein, which is defective in NBS, is a component of the Mre11/RAD50/NBS1 (MRN) complex. This complex plays a major role in the early phase of the cellular response to double strand breaks (DSBs) in the DNA. Among others, MRN is required for timely activation of the protein kinase ATM (A-T mutated), which is disrupted in patients with A-T. Earlier reports show that Atm-deficient mice exhibit severe degeneration of tyrosine hydroxylase (TH)-positive dopaminergic nigro-striatal neurons and their terminals in the striatum. This cell loss is accompanied by a large reduction in immunoreactivity for the dopamine transporter protein (DAT) in the striatum. To test whether Nbs1 inactivation also affects the integrity of the nigro-striatal pathway, we examined this pathway in a murine model with conditional inactivation of the Nbs1 gene in central nervous system (Nbs1-CNS-Δ). We report that this model has a reduction in TH-positive cells in the substantia nigra. This phenomenon was seen at very early age, while Atm−/− mice showed a progressive age-dependent reduction. Furthermore, we observed an age-dependent increase in the level of TH in the striatum of Atm−/− and Nbs1-CNS-Δ mice. In addition to the altered expression of TH, we also found a reduction of DAT in the striatum of both Atm−/− and Nbs1-CNS-Δ mice at 60 days of age. Finally, microglial recruitment and alterations in the levels of various neurotrophic factors were also observed. These results indicate that malfunctioning DNA damage response severely affects the integrity of the nigro-striatal pathway and suggest a new neurodegenerative pathway in Parkinsonian syndromes.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10

Similar content being viewed by others

References

  • Adams KE, Medhurst AL, Dart DA, Lakin ND (2006) Recruitment of ATR to sites of ionising radiation-induced DNA damage requires ATM and components of the MRN protein complex. Oncogene 25:3894–3904

    Article  PubMed  CAS  Google Scholar 

  • Allen DM, van Praag H, Ray J, Weaver Z, Winrow CJ, Carter TA, Braquet R, Harrington E, Ried T, Brown KD, Gage FH, Barlow C (2001) Ataxia telangiectasia mutated is essential during adult neurogenesis. Genes Dev 15:554–566

    Article  PubMed  CAS  Google Scholar 

  • Arai M, Utsunomiya J, Miki Y (2004) Familial breast and ovarian cancers. Int J Clin Oncol 9:270–282

    Article  PubMed  CAS  Google Scholar 

  • Assaf Y, Galron R, Shapira I, Nitzan A, Blumenfeld-Katzir T, Solomon AS, Holdengreber V, Wang ZQ, Shiloh Y, Barzilai A (2008) MRI evidence of white matter damage in a mouse model of Nijmegen breakage syndrome. Exp Neurol 209:181–191

    Article  PubMed  CAS  Google Scholar 

  • Bakkenist CJ, Kastan MB (2003) DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation. Nature 421:499–506

    Article  PubMed  CAS  Google Scholar 

  • Baranes K, Raz-Prag D, Nitzan A, Galron R, Ashery-Padan R, Rotenstreich Y, Assaf Y, Shiloh Y, Wang ZQ, Barzilai A, Solomon AS (2009) Conditional inactivation of the NBS1 gene in the mouse central nervous system leads to neurodegeneration and disorganization of the visual system. Exp Neurol 218:24–32

    Article  PubMed  CAS  Google Scholar 

  • Barlow C, Hirotsune S, Paylor R, Liyanage M, Eckhaus M, Collins F, Shiloh Y, Crawley JN, Ried T, Tagle D, Wynshaw-Boris A (1996) Atm-deficient mice: a paradigm of ataxia telangiectasia. Cell 86:159–171

    Article  PubMed  CAS  Google Scholar 

  • Barlow C, Dennery PA, Shigenaga MK, Smith MA, Morrow JD, Roberts LJ 2nd, Wynshaw-Boris A, Levine RL (1999) Loss of the ataxia-telangiectasia gene product causes oxidative damage in target organs. Proc Natl Acad Sci USA 96:9915–9919

    Article  PubMed  CAS  Google Scholar 

  • Barzilai A (2007) The contribution of the DNA damage response to neuronal viability. Antioxid Redox Signal 9:211–218

    Article  PubMed  CAS  Google Scholar 

  • Barzilai A (2010) DNA damage, neuronal and glial cell death and neurodegeneration. Apoptosis 15:1371–1381

    Article  PubMed  CAS  Google Scholar 

  • Barzilai A, Biton S, Shiloh Y (2008) The role of the DNA damage response in neuronal development, organization and maintenance. DNA Repair (Amst) 7:1010–1027

    Article  CAS  Google Scholar 

  • Bassing CH, Alt FW (2004) The cellular response to general and programmed DNA double strand breaks. DNA Repair (Amst) 3:781–796

    Article  CAS  Google Scholar 

  • Bassing CH, Suh H, Ferguson DO, Chua KF, Manis J, Eckersdorff M, Gleason M, Bronson R, Lee C, Alt FW (2003) Histone H2AX: a dosage-dependent suppressor of oncogenic translocations and tumors. Cell 114:359–370

    Article  PubMed  CAS  Google Scholar 

  • Biton S, Barzilai A, Shiloh Y (2008) The neurological phenotype of ataxia-telangiectasia: solving a persistent puzzle. DNA Repair 7:1028–1038

    Article  PubMed  CAS  Google Scholar 

  • Borghesani PR, Alt FW, Bottaro A, Davidson L, Aksoy S, Rathbun GA, Roberts TM, Swat W, Segal RA, Gu Y (2000) Abnormal development of Purkinje cells and lymphocytes in Atm mutant mice. Proc Natl Acad Sci USA 97:3336–3341

    Article  PubMed  CAS  Google Scholar 

  • Caldecott KW (2004) DNA single-strand breaks and neurodegeneration. DNA Repair (Amst) 3:875–882

    Article  CAS  Google Scholar 

  • Celeste A, Difilippantonio S, Difilippantonio MJ, Fernandez-Capetillo O, Pilch DR, Sedelnikova OA, Eckhaus M, Ried T, Bonner WM, Nussenzweig A (2003) H2AX haploinsufficiency modifies genomic stability and tumor susceptibility. Cell 114:371–383

    Article  PubMed  CAS  Google Scholar 

  • Chadi G, Cao Y, Pettersson RF, Fuxe K (1994) Temporal and spatial increase of astroglial basic fibroblast growth factor synthesis after 6-hydroxydopamine-induced degeneration of the nigrostriatal dopamine neurons. Neuroscience 61:891–910

    Article  PubMed  CAS  Google Scholar 

  • Chen P, Peng C, Luff J, Spring K, Watters D, Bottle S, Furuya S, Lavin MF (2003) Oxidative stress is responsible for deficient survival and dendritogenesis in Purkinje neurons from ataxia-telangiectasia mutated mutant mice. J Neurosci 23:11453–11460

    PubMed  CAS  Google Scholar 

  • Chiesa N, Barlow C, Wynshaw-Boris A, Strata P, Tempia F (2000) Atm-deficient mice Purkinje cells show age-dependent defects in calcium spike bursts and calcium currents. Neuroscience 96:575–583

    Article  PubMed  CAS  Google Scholar 

  • Chun HH, Gatti RA (2004) Ataxia-telangiectasia, an evolving phenotype. DNA Repair (Amst) 3:1187–1196

    Article  CAS  Google Scholar 

  • Cintra A, Cao YH, Oellig C, Tinner B, Bortolotti F, Goldstein M, Pettersson RF, Fuxe K (1991) Basic FGF is present in dopaminergic neurons of the ventral midbrain of the rat. Neuroreport 2:597–600

    Article  PubMed  CAS  Google Scholar 

  • Dar I, Biton S, Shiloh Y, Barzilai A (2006) Analysis of the ataxia telangiectasia mutated-mediated DNA damage response in murine cerebellar neurons. J Neurosci 26:7767–7774

    Article  PubMed  CAS  Google Scholar 

  • Dar I, Yosha G, Elfassy R, Galron R, Wang ZQ, Shiloh Y, Barzilai A (2011) Investigation of the functional link between ATM and NBS1 in the DNA damage response in the mouse cerebellum. J Biol Chem 286:15361–15376

    Article  PubMed  CAS  Google Scholar 

  • Digweed M, Sperling K (2004) Nijmegen breakage syndrome: clinical manifestation of defective response to DNA double-strand breaks. DNA Repair 3:1207–1217

    Article  PubMed  CAS  Google Scholar 

  • Eilam R, Peter Y, Elson A, Rotman G, Shiloh Y, Groner Y, Segal M (1998) Selective loss of dopaminergic nigro-striatal neurons in brains of Atm-deficient mice. Proc Natl Acad Sci USA 95:12653–12656

    Article  PubMed  CAS  Google Scholar 

  • Eilam R, Peter Y, Groner Y, Segal M (2003) Late degeneration of nigro-striatal neurons in ATM−/− mice. Neuroscience 121:83–98

    Article  PubMed  CAS  Google Scholar 

  • El Khoury J, Toft M, Hickman SE, Means TK, Terada K, Geula C, Luster AD (2007) Ccr2 deficiency impairs microglial accumulation and accelerates progression of Alzheimer-like disease. Nat Med 13:432–438

    Article  PubMed  CAS  Google Scholar 

  • Elson A, Wang Y, Daugherty CJ, Morton CC, Zhou F, Campos-Torres J, Leder P (1996) Pleiotropic defects in ataxia-telangiectasia protein-deficient mice. Proc Natl Acad Sci USA 93:13084–13089

    Article  PubMed  CAS  Google Scholar 

  • Escartin C, Bonvento G (2008) Targeted activation of astrocytes: a potential neuroprotective strategy. Mol Neurobiol 38:231–241

    Article  PubMed  CAS  Google Scholar 

  • Falck J, Coates J, Jackson SP (2005) Conserved modes of recruitment of ATM, ATR and DNA-PKcs to sites of DNA damage. Nature 434:605–611

    Article  PubMed  CAS  Google Scholar 

  • Fallon JH, Moore RY (1978) Catecholamine innervation of the basal forebrain. IV. Topography of the dopamine projection to the basal forebrain and neostriatum. J Comp Neurol 180:545–580

    Article  PubMed  CAS  Google Scholar 

  • Farfara D, Lifshitz V, Frenkel D (2008) Neuroprotective and neurotoxic properties of glial cells in the pathogenesis of Alzheimer's disease. J Cell Mol Med 12:762–780

    Article  PubMed  CAS  Google Scholar 

  • Frappart PO, Tong WM, Demuth I, Radovanovic I, Herceg Z, Aguzzi A, Digweed M, Wang ZQ (2005) An essential function for NBS1 in the prevention of ataxia and cerebellar defects. Nat Med 11:538–544

    Article  PubMed  CAS  Google Scholar 

  • Gaig C, Tolosa E (2009) When does Parkinson's disease begin? Mov Disord 24(Suppl 2):S656–S664

    Article  PubMed  Google Scholar 

  • Galron R, Gruber R, Lifshitz V, Lu H, Kirshner M, Ziv N, Wang ZQ, Shiloh Y, Barzilai A, Frenkel D (2011) Astrocyte dysfunction associated with cerebellar attrition in a nijmegen breakage syndrome animal model. J Mol Neurosci (in press)

  • Giaume C, Kirchhoff F, Matute C, Reichenbach A, Verkhratsky A (2007) Glia: the fulcrum of brain diseases. Cell Death Differ 14:1324–1335

    Article  PubMed  CAS  Google Scholar 

  • Gueven N, Luff J, Peng C, Hosokawa K, Bottle SE, Lavin MF (2006) Dramatic extension of tumor latency and correction of neurobehavioral phenotype in Atm-mutant mice with a nitroxide antioxidant. Free Radic Biol Med 41:992–1000

    Article  PubMed  CAS  Google Scholar 

  • Hanisch UK, Kettenmann H (2007) Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci 10:1387–1394

    Article  PubMed  CAS  Google Scholar 

  • Harrison JC, Haber JE (2006) Surviving the breakup: the DNA damage checkpoint. Annu Rev Genet 40:209–235

    Article  PubMed  CAS  Google Scholar 

  • Hirano R, Interthal H, Huang C, Nakamura T, Deguchi K, Choi K, Bhattacharjee MB, Arimura K, Umehara F, Izumo S, Northrop JL, Salih MA, Inoue K, Armstrong DL, Champoux JJ, Takashima H, Boerkoel CF (2007) Spinocerebellar ataxia with axonal neuropathy: consequence of a Tdp1 recessive neomorphic mutation? EMBO J 26:4732–4743

    Article  PubMed  CAS  Google Scholar 

  • Ho A, Gore AC, Weickert CS, Blum M (1995) Glutamate regulation of GDNF gene expression in the striatum and primary striatal astrocytes. Neuroreport 6:1454–1458

    Article  PubMed  CAS  Google Scholar 

  • Hu B, Han W, Wu L, Feng H, Liu X, Zhang L, Xu A, Hei TK, Yu Z (2005) In situ visualization of DSBs to assess the extranuclear/extracellular effects induced by low-dose alpha-particle irradiation. Radiat Res 164:286–291

    Article  PubMed  CAS  Google Scholar 

  • Hurley PJ, Bunz F (2007) ATM and ATR: components of an integrated circuit. Cell Cycle 6:414–417

    Article  PubMed  CAS  Google Scholar 

  • Kalehua AN, Nagel JE, Whelchel LM, Gides JJ, Pyle RS, Smith RJ, Kusiak JW, Taub DD (2004) Monocyte chemoattractant protein-1 and macrophage inflammatory protein-2 are involved in both excitotoxin-induced neurodegeneration and regeneration. Exp Cell Res 297:197–211

    Article  PubMed  CAS  Google Scholar 

  • Kamsler A, Daily D, Hochman A, Stern N, Shiloh Y, Rotman G, Barzilai A (2001) Increased oxidative stress in ataxia telangiectasia evidenced by alterations in redox state of brains from Atm-deficient mice. Cancer Res 61:1849–1854

    PubMed  CAS  Google Scholar 

  • Karakaya S, Kipp M, Beyer C (2007) Oestrogen regulates the expression and function of dopamine transporters in astrocytes of the nigrostriatal system. J Neuroendocrinol 19:682–690

    Article  PubMed  CAS  Google Scholar 

  • Kim JE, Minter-Dykhouse K, Chen J (2006) Signaling networks controlled by the MRN complex and MDC1 during early DNA damage responses. Mol Carcinog 45:403–408

    Article  PubMed  CAS  Google Scholar 

  • Kruger A, Ralser M (2011) ATM is a redox sensor linking genome stability and carbon metabolism. Sci Signal 4:pe17

    Article  PubMed  Google Scholar 

  • Kuljis RO, Xu Y, Aguila MC, Baltimore D (1997) Degeneration of neurons, synapses, and neuropil and glial activation in a murine Atm knockout model of ataxia-telangiectasia. Proc Natl Acad Sci USA 94:12688–12693

    Article  PubMed  CAS  Google Scholar 

  • Lavin MF (2007) ATM and the Mre11 complex combine to recognize and signal DNA double-strand breaks. Oncogene 26:7749–7758

    Article  PubMed  CAS  Google Scholar 

  • Lavin MF (2008) Ataxia-telangiectasia: from a rare disorder to a paradigm for cell signalling and cancer. Nat Rev Mol Cell Biol 9:759–769

    Article  PubMed  CAS  Google Scholar 

  • Lee Y, McKinnon PJ (2007) Responding to DNA double strand breaks in the nervous system. Neuroscience 145:1365–1374

    Article  PubMed  CAS  Google Scholar 

  • Lee JH, Paull TT (2007) Activation and regulation of ATM kinase activity in response to DNA double-strand breaks. Oncogene 26:7741–7748

    Article  PubMed  CAS  Google Scholar 

  • Levine-Small N, Yekutieli Z, Aljadeff J, Boccaletti S, Ben-Jacob E, Barzilai A (2011) Reduced synchronization persistence in neural networks derived from Atm-deficient mice. Front Neurosci 5:46

    Article  PubMed  Google Scholar 

  • Li J, Han YR, Plummer MR, Herrup K (2009) Cytoplasmic ATM in neurons modulates synaptic function. Curr Biol 19:2091–2096

    Article  PubMed  CAS  Google Scholar 

  • Lieber MR, Ma Y, Pannicke U, Schwarz K (2004) The mechanism of vertebrate nonhomologous DNA end joining and its role in V(D)J recombination. DNA Repair (Amst) 3:817–826

    Article  CAS  Google Scholar 

  • Ma DK, Ming GL, Song H (2005) Glial influences on neural stem cell development: cellular niches for adult neurogenesis. Curr Opin Neurobiol 15:514–520

    Article  PubMed  CAS  Google Scholar 

  • Melchers A, Stockl L, Radszewski J, Anders M, Krenzlin H, Kalischke C, Scholz R, Jordan A, Nebrich G, Klose J, Sperling K, Digweed M, Demuth I (2009) A systematic proteomic study of irradiated DNA repair deficient Nbn-mice. PLoS One 4:e5423

    Article  PubMed  Google Scholar 

  • Mount HT, Martel JC, Fluit P, Wu Y, Gallo-Hendrikx E, Cosi C, Marien MR (2004) Progressive sensorimotor impairment is not associated with reduced dopamine and high energy phosphate donors in a model of ataxia-telangiectasia. J Neurochem 88:1449–1454

    Article  PubMed  CAS  Google Scholar 

  • Myers JS, Cortez D (2006) Rapid activation of ATR by ionizing radiation requires ATM and Mre11. J Biol Chem 281:9346–9350

    Article  PubMed  CAS  Google Scholar 

  • Narod SA, Foulkes WD (2004) BRCA1 and BRCA2: 1994 and beyond. Nat Rev Cancer 4:665–676

    Article  PubMed  CAS  Google Scholar 

  • Nimmerjahn A (2009) Astrocytes going live: advances and challenges. J Physiol 587:1639–1647

    Article  PubMed  CAS  Google Scholar 

  • O'Driscoll M, Gennery AR, Seidel J, Concannon P, Jeggo PA (2004) An overview of three new disorders associated with genetic instability: LIG4 syndrome, RS-SCID and ATR-Seckel syndrome. DNA Repair (Amst) 3:1227–1235

    Article  Google Scholar 

  • Rotman G, Shiloh Y (1997) Ataxia-telangiectasia: is ATM a sensor of oxidative damage and stress? Bioessays 19:911–917

    Article  PubMed  CAS  Google Scholar 

  • Shechter D, Costanzo V, Gautier J (2004) Regulation of DNA replication by ATR: signaling in response to DNA intermediates. DNA Repair (Amst) 3:901–908

    Article  CAS  Google Scholar 

  • Shiloh Y (2003) ATM and related protein kinases: safeguarding genome integrity. Nat Rev Cancer 3:155–168

    Article  PubMed  CAS  Google Scholar 

  • Shiloh Y (2006) The ATM-mediated DNA-damage response: taking shape. Trends Biochem Sci 31:402–410

    Article  PubMed  CAS  Google Scholar 

  • Shiloh Y, Lehmann AR (2004) Maintaining integrity. Nat Cell Biol 6:923–928

    Article  PubMed  CAS  Google Scholar 

  • Shull ER, Lee Y, Nakane H, Stracker TH, Zhao J, Russell HR, Petrini JH, McKinnon PJ (2009) Differential DNA damage signaling accounts for distinct neural apoptotic responses in ATLD and NBS. Genes Dev 23:171–180

    Article  PubMed  CAS  Google Scholar 

  • Sofroniew MV, Vinters HV (2010) Astrocytes: biology and pathology. Acta Neuropathol 119:7–35

    Article  PubMed  Google Scholar 

  • Staalesen V, Falck J, Geisler S, Bartkova J, Borresen-Dale AL, Lukas J, Lillehaug JR, Bartek J, Lonning PE (2004) Alternative splicing and mutation status of CHEK2 in stage III breast cancer. Oncogene 23:8535–8544

    Article  PubMed  CAS  Google Scholar 

  • Stern N, Hochman A, Zemach N, Weizman N, Hammel I, Shiloh Y, Rotman G, Barzilai A (2002) Accumulation of DNA damage and reduced levels of nicotine adenine dinucleotide in the brains of Atm-deficient mice. J Biol Chem 277:602–608

    Article  PubMed  CAS  Google Scholar 

  • Stiff T, Reis C, Alderton GK, Woodbine L, O'Driscoll M, Jeggo PA (2005) Nbs1 is required for ATR-dependent phosphorylation events. EMBO J 24:199–208

    Article  PubMed  CAS  Google Scholar 

  • Streit WJ (2006) Microglial senescence: does the brain's immune system have an expiration date? Trends Neurosci 29:506–510

    Article  PubMed  CAS  Google Scholar 

  • Stromberg I, Bjorklund L, Johansson M, Tomac A, Collins F, Olson L, Hoffer B, Humpel C (1993) Glial cell line-derived neurotrophic factor is expressed in the developing but not adult striatum and stimulates developing dopamine neurons in vivo. Exp Neurol 124:401–412

    Article  PubMed  CAS  Google Scholar 

  • Stucki M, Jackson SP (2004) MDC1/NFBD1: a key regulator of the DNA damage response in higher eukaryotes. DNA Repair (Amst) 3:953–957

    Article  CAS  Google Scholar 

  • Stucki M, Jackson SP (2006) gammaH2AX and MDC1: anchoring the DNA-damage-response machinery to broken chromosomes. DNA Repair (Amst) 5:534–543

    Article  CAS  Google Scholar 

  • Su TT (2006) Cellular responses to DNA damage: one signal, multiple choices. Annu Rev Genet 40:187–208

    Article  PubMed  CAS  Google Scholar 

  • Sugawara M, Wada C, Okawa S, Kobayashi M, Sageshima M, Imota T, Toyoshima I (2008) Purkinje cell loss in the cerebellar flocculus in patients with ataxia with ocular motor apraxia type 1/early-onset ataxia with ocular motor apraxia and hypoalbuminemia. Eur Neurol 59:18–23

    Article  PubMed  Google Scholar 

  • Swanson RA, Ying W, Kauppinen TM (2004) Astrocyte influences on ischemic neuronal death. Curr Mol Med 4:193–205

    Article  PubMed  CAS  Google Scholar 

  • Thompson LH, West MG (2000) XRCC1 keeps DNA from getting stranded. Mutat Res 459:1–18

    PubMed  CAS  Google Scholar 

  • Torres GE (2006) The dopamine transporter proteome. J Neurochem 97(Suppl 1):3–10

    Article  PubMed  CAS  Google Scholar 

  • Tort F, Hernandez S, Bea S, Camacho E, Fernandez V, Esteller M, Fraga MF, Burek C, Rosenwald A, Hernandez L, Campo E (2005) Checkpoint kinase 1 (CHK1) protein and mRNA expression is downregulated in aggressive variants of human lymphoid neoplasms. Leukemia 19:112–117

    PubMed  CAS  Google Scholar 

  • Uziel T, Lerenthal Y, Moyal L, Andegeko Y, Mittelman L, Shiloh Y (2003) Requirement of the MRN complex for ATM activation by DNA damage. EMBO J 22:5612–5621

    Article  PubMed  CAS  Google Scholar 

  • Van Den Bosch M, Bree RT, Lowndes NF (2003) The MRN complex: coordinating and mediating the response to broken chromosomes. EMBO Rep 4:844–849

    Article  PubMed  Google Scholar 

  • Varley JM (2003) Germline TP53 mutations and Li-Fraumeni syndrome. Hum Mutat 21:313–320

    Article  PubMed  CAS  Google Scholar 

  • Varley J, Haber DA (2003) Familial breast cancer and the hCHK2 1100delC mutation: assessing cancer risk. Breast Cancer Res 5:123–125

    Article  PubMed  CAS  Google Scholar 

  • Wang J, Bankiewicz KS, Plunkett RJ, Oldfield EH (1994) Intrastriatal implantation of interleukin-1. Reduction of parkinsonism in rats by enhancing neuronal sprouting from residual dopaminergic neurons in the ventral tegmental area of the midbrain. J Neurosurg 80:484–490

    Article  PubMed  CAS  Google Scholar 

  • Watters DJ (2003) Oxidative stress in ataxia telangiectasia. Redox Rep 8:23–29

    Article  PubMed  CAS  Google Scholar 

  • Watters D, Kedar P, Spring K, Bjorkman J, Chen P, Gatei M, Birrell G, Garrone B, Srinivasa P, Crane DI, Lavin MF (1999) Localization of a portion of extranuclear ATM to peroxisomes. J Biol Chem 274:34277–34282

    Article  PubMed  CAS  Google Scholar 

  • Wyman C, Kanaar R (2006) DNA double-strand break repair: all's well that ends well. Annu Rev Genet 40:363–383

    Article  PubMed  CAS  Google Scholar 

  • Xu Y, Ashley T, Brainerd EE, Bronson RT, Meyn MS, Baltimore D (1996) Targeted disruption of ATM leads to growth retardation, chromosomal fragmentation during meiosis, immune defects, and thymic lymphoma. Genes Dev 10:2411–2422

    Article  PubMed  CAS  Google Scholar 

  • Zgheib O, Huyen Y, DiTullio RA Jr, Snyder A, Venere M, Stavridi ES, Halazonetis TD (2005) ATM signaling and 53BP1. Radiother Oncol 76:119–122

    Article  PubMed  CAS  Google Scholar 

  • Zhang J, Powell SN (2005) The role of the BRCA1 tumor suppressor in DNA double-strand break repair. Mol Cancer Res 3:531–539

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Neurobiology, George S. Wise, Faculty of Life Sciences, Tel Aviv University, Tel Aviv, 69978, Israel

    Michal Kirshner, Ronit Galron, Dan Frenkel, Gil Mandelbaum & Ari Barzilai

  2. The David and Inez Myers Laboratory for Cancer Genetics, Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, 69978, Israel

    Yosef Shiloh

  3. Leibniz Institute for Age Research—Fritz Lipmann Institute e.V, Jena, Germany

    Zhao-Qi Wang

  4. Friedrich-Schiller-University of Jena, 07745, Jena, Germany

    Zhao-Qi Wang

Authors
  1. Michal Kirshner
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ronit Galron
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Dan Frenkel
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Gil Mandelbaum
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yosef Shiloh
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Zhao-Qi Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ari Barzilai
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ari Barzilai.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kirshner, M., Galron, R., Frenkel, D. et al. Malfunctioning DNA Damage Response (DDR) Leads to the Degeneration of Nigro-Striatal Pathway in Mouse Brain. J Mol Neurosci 46, 554–568 (2012). https://doi.org/10.1007/s12031-011-9643-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12031-011-9643-y

Keywords

Search

Navigation