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Neurodegeneration: Nicked to Death

2007; Elsevier BV; Volume: 17; Issue: 2 Linguagem: Inglês

10.1016/j.cub.2006.12.012

1879-0445

David M. Wilson, Mark P. Mattson,

Microtubule and mitosis dynamics

Ataxia oculomotor apraxia-1 is a neurological disorder that arises from mutations in the gene encoding the protein aprataxin. A recent study demonstrates that aprataxin is critical for the processing of obstructive DNA termini, suggesting a broader role for DNA single-strand break repair in neurodegenerative disease. Ataxia oculomotor apraxia-1 is a neurological disorder that arises from mutations in the gene encoding the protein aprataxin. A recent study demonstrates that aprataxin is critical for the processing of obstructive DNA termini, suggesting a broader role for DNA single-strand break repair in neurodegenerative disease. Neurons are postmitotic cells that must survive and function properly for the entire lifetime of the organism. Because they cannot be replaced and are subjected to high metabolic stress, mechanisms for coping with damaged molecules may be particularly important in these cells. Indeed, human neurodegenerative disorders, such as Alzheimer's and Parkinson's diseases, involve the abnormal accumulation of damaged proteins [1Forloni G. Terreni L. Bertani I. Fogliarino S. Invernizzi R. Assini A. Ribizzi G. Negro A. Calabrese E. Volonte M.A. et al.Protein misfolding in Alzheimer's and Parkinson's disease: genetics and molecular mechanisms.Neurobiol. Aging. 2002; 23: 957-976Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar], and other syndromes, such as ataxia telangiectasia (AT), have been associated with defects in DNA-damage processing [2Rolig R.L. McKinnon P.J. Linking DNA damage and neurodegeneration.Trends Neurosci. 2000; 23: 417-424Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar]. Work from El-Khamisy et al.[3El-Khamisy S.F. Saifi G.M. Weinfeld M. Johansson F. Helleday T. Lupski J.R. Caldecott K.W. Defective DNA single-strand break repair in spinocerebellar ataxia with axonal neuropathy-1.Nature. 2005; 434: 108-113Crossref PubMed Scopus (324) Google Scholar] and a more recent study by Ahel et al.[4Ahel I. Rass U. El-Khamisy S.F. Katyal S. Clements P.M. McKinnon P.J. Caldecott K.W. West S.C. The neurodegenerative disease protein aprataxin resolves abortive DNA ligation intermediates.Nature. 2006; 443: 713-716Crossref PubMed Scopus (262) Google Scholar] have revealed that inefficient repair of DNA single-strand breaks (SSBs) can give rise to neurodegenerative disease, in particular, spinocerebellar ataxia with axonal neuropathy-1 (SCAN1) and ataxia oculomotor apraxia-1 (AOA1), respectively. These data provide evidence that non-replicating, post-mitotic neurons are particularly sensitive to the accumulation of DNA SSBs. SSBs, one of the most common lesions formed in chromosomal DNA, are generated by the attack of reactive oxygen species [5Evans M.D. Dizdaroglu M. Cooke M.S. Oxidative DNA damage and disease: induction, repair and significance.Mutat. Res. 2004; 567: 1-61Crossref PubMed Scopus (955) Google Scholar] or as natural intermediates during certain DNA transactions, including repair and replication [6Connelly J.C. Leach D.R. Repair of DNA covalently linked to protein.Mol. Cell. 2004; 13: 307-316Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar]. In both instances, SSBs can harbor non-conventional 3′ or 5′ termini, such as phosphates, phosphoglycolates, or trapped polypeptides, which present obstacles to polymerization and ligation activities. To remove such obstructions, cells undergo SSB repair, a process related to the more classical base excision repair (BER) pathway [7Thompson L.H. West M.G. XRCC1 keeps DNA from getting stranded.Mutat. Res. 2000; 459: 1-18Crossref PubMed Scopus (394) Google Scholar]. The SSB repair proteins excise terminal blocking groups (Figure 1), permitting gap-filling synthesis and sealing of the final nick in DNA. AOA1 and SCAN1 are hereditary autosomal recessive ataxias affecting primarily motor coordination, i.e. gaze, speech, gait and balance [8Takashima H. Boerkoel C.F. John J. Saifi G.M. Salih M.A. Armstrong D. Mao Y. Quiocho F.A. Roa B.B. Nakagawa M. et al.Mutation of TDP1, encoding a topoisomerase I-dependent DNA damage repair enzyme, in spinocerebellar ataxia with axonal neuropathy.Nat. Genet. 2002; 32: 267-272Crossref PubMed Scopus (399) Google Scholar, 9Moreira M.C. Barbot C. Tachi N. Kozuka N. Uchida E. Gibson T. Mendonca P. Costa M. Barros J. Yanagisawa T. et al.The gene mutated in ataxia-ocular apraxia 1 encodes the new HIT/Zn-finger protein aprataxin.Nat. Genet. 2001; 29: 189-193Crossref PubMed Scopus (360) Google Scholar, 10Date H. Onodera O. Tanaka H. Iwabuchi K. Uekawa K. Igarashi S. Koike R. Hiroi T. Yuasa T. Awaya Y. et al.Early-onset ataxia with ocular motor apraxia and hypoalbuminemia is caused by mutations in a new HIT superfamily gene.Nat. Genet. 2001; 29: 184-188Crossref PubMed Scopus (317) Google Scholar]. Unlike patients suffering from other DNA-repair-related disorders characterized by neurological dysfunction, such as AT [2Rolig R.L. McKinnon P.J. Linking DNA damage and neurodegeneration.Trends Neurosci. 2000; 23: 417-424Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar], patients suffering from AOA1 and SCAN1 lack non-neurological symptoms, most notably the increased cancer incidence. The recent cloning and characterization of the genes defective in AOA1 and SCAN1 has shed light on why non-replicating neuronal cells may be exquisitely sensitive to the accumulation of certain DNA intermediates. The gene mutated in SCAN1 encodes the protein tyrosyl-DNA phosphodiesterase 1 (TDP1) [8Takashima H. Boerkoel C.F. John J. Saifi G.M. Salih M.A. Armstrong D. Mao Y. Quiocho F.A. Roa B.B. Nakagawa M. et al.Mutation of TDP1, encoding a topoisomerase I-dependent DNA damage repair enzyme, in spinocerebellar ataxia with axonal neuropathy.Nat. Genet. 2002; 32: 267-272Crossref PubMed Scopus (399) Google Scholar], which was shown to be the primary enzyme for excising covalently linked 3′-topoisomerase I (TOPO1) –DNA intermediates [11Pouliot J.J. Yao K.C. Robertson C.A. Nash H.A. Yeast gene for a Tyr-DNA phosphodiesterase that repairs topoisomerase I complexes.Science. 1999; 286: 552-555Crossref PubMed Scopus (291) Google Scholar]. TOPO1 binds and cleaves one strand of DNA via a transient covalent protein–nucleic acid complex to relieve topological strains (i.e. supercoils) generated during repair, replication or recombination. However, the TOPO1–DNA intermediate can become ‘trapped’ either when in close proximity to DNA damage, such as oxidative lesions, or upon exposure of cells to the chemotherapeutic agent camptothecin [6Connelly J.C. Leach D.R. Repair of DNA covalently linked to protein.Mol. Cell. 2004; 13: 307-316Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar]. TDP1 removes the covalently linked 3′-TOPO1 protein moiety, leaving behind a 3′-phosphate group, which is excised by polynucleotide kinase/phosphatase (PNKP) [3El-Khamisy S.F. Saifi G.M. Weinfeld M. Johansson F. Helleday T. Lupski J.R. Caldecott K.W. Defective DNA single-strand break repair in spinocerebellar ataxia with axonal neuropathy-1.Nature. 2005; 434: 108-113Crossref PubMed Scopus (324) Google Scholar]. These enzymatic steps generate a normal 3′-hydroxyl end, which is suitable for polymerase extension and subsequent ligation. The studies of El-Khamisy et al.[3El-Khamisy S.F. Saifi G.M. Weinfeld M. Johansson F. Helleday T. Lupski J.R. Caldecott K.W. Defective DNA single-strand break repair in spinocerebellar ataxia with axonal neuropathy-1.Nature. 2005; 434: 108-113Crossref PubMed Scopus (324) Google Scholar] indicate that cells from SCAN1 patients are unable to process specific 3′-obstructive termini efficiently. El-Khamisy and colleagues [3El-Khamisy S.F. Saifi G.M. Weinfeld M. Johansson F. Helleday T. Lupski J.R. Caldecott K.W. Defective DNA single-strand break repair in spinocerebellar ataxia with axonal neuropathy-1.Nature. 2005; 434: 108-113Crossref PubMed Scopus (324) Google Scholar] found that SCAN1 cells are defective in the repair of camptothecin-induced SSBs that arise independently of DNA replication. Moreover, the authors report that TDP1 directly interacts with DNA ligase IIIα (LIG3α), a partner of the SSB repair protein XRCC1, and exists in a complex with LIG3α, XRCC1, and PNKP that is capable of repairing tyrosyl-containing oligonucleotide substrates that mimic TOPO1–DNA SSBs. While a similar multi-protein complex was found in extracts from SCAN1 cells, the disease-causing TDP1 mutations render the phosphodiesterase incapable of excising 3′-tyrosyl blocking groups from DNA [3El-Khamisy S.F. Saifi G.M. Weinfeld M. Johansson F. Helleday T. Lupski J.R. Caldecott K.W. Defective DNA single-strand break repair in spinocerebellar ataxia with axonal neuropathy-1.Nature. 2005; 434: 108-113Crossref PubMed Scopus (324) Google Scholar, 8Takashima H. Boerkoel C.F. John J. Saifi G.M. Salih M.A. Armstrong D. Mao Y. Quiocho F.A. Roa B.B. Nakagawa M. et al.Mutation of TDP1, encoding a topoisomerase I-dependent DNA damage repair enzyme, in spinocerebellar ataxia with axonal neuropathy.Nat. Genet. 2002; 32: 267-272Crossref PubMed Scopus (399) Google Scholar]. It was postulated that the accumulation of obstructive 3′-terminal SSBs would impair transcriptional efficacy and induce cell death. Ahel and colleagues [4Ahel I. Rass U. El-Khamisy S.F. Katyal S. Clements P.M. McKinnon P.J. Caldecott K.W. West S.C. The neurodegenerative disease protein aprataxin resolves abortive DNA ligation intermediates.Nature. 2006; 443: 713-716Crossref PubMed Scopus (262) Google Scholar] have now expanded the concept that defects in SSB repair can lead selectively to neuronal cell death. The gene defective in AOA1 encodes the protein aprataxin, which contains three conserved domains: a forkhead-associated interaction module; a histidine triad (HIT) domain found in nucleotide hydrolases and transferases; and a DNA-binding C2H2 zinc-finger motif [9Moreira M.C. Barbot C. Tachi N. Kozuka N. Uchida E. Gibson T. Mendonca P. Costa M. Barros J. Yanagisawa T. et al.The gene mutated in ataxia-ocular apraxia 1 encodes the new HIT/Zn-finger protein aprataxin.Nat. Genet. 2001; 29: 189-193Crossref PubMed Scopus (360) Google Scholar, 10Date H. Onodera O. Tanaka H. Iwabuchi K. Uekawa K. Igarashi S. Koike R. Hiroi T. Yuasa T. Awaya Y. et al.Early-onset ataxia with ocular motor apraxia and hypoalbuminemia is caused by mutations in a new HIT superfamily gene.Nat. Genet. 2001; 29: 184-188Crossref PubMed Scopus (317) Google Scholar]. While prior investigations had revealed interactions of aprataxin with proteins involved in SSB repair, namely XRCC1 and poly(ADP-ribose) polymerase 1 (PARP1) [12Gueven N. Becherel O.J. Kijas A.W. Chen P. Howe O. Rudolph J.H. Gatti R. Date H. Onodera O. Taucher-Scholz G. et al.Aprataxin, a novel protein that protects against genotoxic stress.Hum. Mol. Genet. 2004; 13: 1081-1093Crossref PubMed Scopus (136) Google Scholar, 13Clements P.M. Breslin C. Deeks E.D. Byrd P.J. Ju L. Bieganowski P. Brenner C. Moreira M.C. Taylor A.M. Caldecott K.W. The ataxia-oculomotor apraxia 1 gene product has a role distinct from ATM and interacts with the DNA strand break repair proteins XRCC1 and XRCC4.DNA Repair (Amst). 2004; 3: 1493-1502Crossref PubMed Scopus (154) Google Scholar], a biochemical activity for aprataxin in this repair response had not been identified. Ahel and colleagues [4Ahel I. Rass U. El-Khamisy S.F. Katyal S. Clements P.M. McKinnon P.J. Caldecott K.W. West S.C. The neurodegenerative disease protein aprataxin resolves abortive DNA ligation intermediates.Nature. 2006; 443: 713-716Crossref PubMed Scopus (262) Google Scholar], recognizing that the aprataxin-binding proteins XRCC1 and XRCC4 are stable interaction partners of DNA ligases [13Clements P.M. Breslin C. Deeks E.D. Byrd P.J. Ju L. Bieganowski P. Brenner C. Moreira M.C. Taylor A.M. Caldecott K.W. The ataxia-oculomotor apraxia 1 gene product has a role distinct from ATM and interacts with the DNA strand break repair proteins XRCC1 and XRCC4.DNA Repair (Amst). 2004; 3: 1493-1502Crossref PubMed Scopus (154) Google Scholar], examined whether aprataxin might release 5′-AMP intermediates that remain after failed ligation reactions. Indeed, recombinant aprataxin was found to excise AMP residues linked to the 5′-terminal phosphate group of synthetic DNA substrates, a step necessary for subsequent repair events in vitro. In addition, vertebrate cell extracts lacking aprataxin, including those from AOA1 lymphoblastoid cells, were defective in the removal of DNA-adenylates formed by abortive ligation reactions, which occur more frequently at non-conventional oxidative SSBs. The authors propose that the inability of aprataxin to act as an AMP-hydrolase results in the accumulation of DNA strand breaks that ultimately impair normal cellular physiology and lead to neuronal cell death. Notably, the disease-causing mutations in APTX are truncating and missense in nature, and are largely confined to the HIT domain [9Moreira M.C. Barbot C. Tachi N. Kozuka N. Uchida E. Gibson T. Mendonca P. Costa M. Barros J. Yanagisawa T. et al.The gene mutated in ataxia-ocular apraxia 1 encodes the new HIT/Zn-finger protein aprataxin.Nat. Genet. 2001; 29: 189-193Crossref PubMed Scopus (360) Google Scholar, 10Date H. Onodera O. Tanaka H. Iwabuchi K. Uekawa K. Igarashi S. Koike R. Hiroi T. Yuasa T. Awaya Y. et al.Early-onset ataxia with ocular motor apraxia and hypoalbuminemia is caused by mutations in a new HIT superfamily gene.Nat. Genet. 2001; 29: 184-188Crossref PubMed Scopus (317) Google Scholar]. The current data leave two key issues unresolved. First, why do AOA1 and SCAN1 DNA repair defects lead to neurological dysfunction, yet not cancer susceptibility? One possibility is that non-dividing cells accumulate SSBs, which ultimately lead to impaired transcriptional programming and eventual cell death (Figure 1). Indeed, SSBs are effective blocks to RNA polymerase progression [14Kathe S.D. Shen G.P. Wallace S.S. Single-stranded breaks in DNA but not oxidative DNA base damages block transcriptional elongation by RNA polymerase II in HeLa cell nuclear extracts.J. Biol. Chem. 2004; 279: 18511-18520Crossref PubMed Scopus (103) Google Scholar]. Furthermore, due to their unusually high rates of oxygen metabolism, neuronal cells probably accumulate more trapped 3′-TOPO1 and 5′-AMP intermediates due to the production of oxidative DNA damage. Conversely, in dividing cells, unrepaired SSBs would give rise upon replication fork collapse to DNA double-strand breaks, which would presumably be efficiently and accurately repaired by homologous recombination (Figure 1). Thus, while a broad range of DNA intermediates can drive neuronal cell loss and neurodegenerative disease, the SSBs of AOA1 and SCAN1 are apparently not particularly mutagenic in replicating tissue, unlike the double-strand breaks associated with AT and Nijmegen breakage syndrome, or the bulky, helix-distorting lesions found in xeroderma pigmentosum, or the unresolved complex DNA structures in Fanconi anemia, Werner syndrome, Bloom syndrome and Rothmund Thomson syndrome [2Rolig R.L. McKinnon P.J. Linking DNA damage and neurodegeneration.Trends Neurosci. 2000; 23: 417-424Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar]. Future studies need to address specifically whether SSBs in fact accumulate in the neuronal cells of AOA1 and SCAN1 patients. Interestingly, individuals suffering from the disorder Cockayne syndrome are also not cancer-prone, yet exhibit gross developmental abnormalities and neurological deficits [15Cleaver J.E. Cancer in xeroderma pigmentosum and related disorders of DNA repair.Nat. Rev. Cancer. 2005; 5: 564-573Crossref PubMed Scopus (322) Google Scholar]. A defect in facilitating transcription or repairing endogenous DNA damage, or both, may be responsible for the selective loss of neuronal tissue in this disease. Second, is it a general feature that defects in SSB repair lead to enhanced neuronal cell death? Mice devoid of the major gap-filling DNA polymerase, Polβ, exhibit defective neurogenesis characterized by apoptotic cell death in the developing central and peripheral nervous systems that ultimately leads to neonatal lethality [16Sugo N. Aratani Y. Nagashima Y. Kubota Y. Koyama H. Neonatal lethality with abnormal neurogenesis in mice deficient in DNA polymerase beta.EMBO J. 2000; 19: 1397-1404Crossref PubMed Google Scholar]. Model systems impaired in other SSB repair steps could also be examined to interrogate this hypothesis further. For instance, XRCC1 is a non-enzymatic scaffold protein that facilitates efficient BER/SSB repair [7Thompson L.H. West M.G. XRCC1 keeps DNA from getting stranded.Mutat. Res. 2000; 459: 1-18Crossref PubMed Scopus (394) Google Scholar], so deficiencies in this protein should lead to increased neuronal cell death, and accompanying neurological dysfunction. Defects in PNKP, which as noted above operates in the same pathway as TDP1, should likewise result in increased neurological deficits. Suggestive of a role for these proteins in maintaining neuronal cell viability is the fact that camptothecin-induced strand breaks accumulate in XRCC1-deficient CHO cells and in PNKP-depleted human A549 cells at levels similar to those detected in SCAN1 cells [3El-Khamisy S.F. Saifi G.M. Weinfeld M. Johansson F. Helleday T. Lupski J.R. Caldecott K.W. Defective DNA single-strand break repair in spinocerebellar ataxia with axonal neuropathy-1.Nature. 2005; 434: 108-113Crossref PubMed Scopus (324) Google Scholar]. Whether or not deficits in these repair proteins will strictly affect neurodegeneration, and not cancer susceptibility, awaits investigation. In this regard, it is noteworthy that defects in the strand break response protein, PARP1, lead to both neurological abnormalities and cancer predisposition in mouse models [17Koh D.W. Dawson T.M. Dawson V.L. Poly(ADP-ribosyl)ation regulation of life and death in the nervous system.Cell Mol. Life Sci. 2005; 62: 760-768Crossref PubMed Scopus (61) Google Scholar]. Finally, there is emerging evidence that defects in the core BER participants, i.e. some of the DNA glycosylases, which remove endogenous base modifications, and the abasic (AP) endonuclease APE1, which initiates excision of AP sites in DNA as well as certain 3′-damages, contribute to neuronal cell survival, at least in culture [18Wilson III, D.M. McNeill D.R. Base excision repair and the central nervous system.Neuroscience. 2006; (Epub ahead of print)Google Scholar]. We close by mentioning a few considerations relevant to the discussion above. First, DNA repair systems differ qualitatively and quantitatively between dividing and non-dividing cells [19Nouspikel T. Hanawalt P.C. DNA repair in terminally differentiated cells.DNA Repair (Amst). 2002; 1: 59-75Crossref PubMed Scopus (206) Google Scholar]. In particular, global DNA repair machinery is downregulated in differentiated neurons, whereas the machinery for repairing transcribed sequences is maintained or upregulated. Second, perturbations in DNA repair more subtle than those caused by genetic mutations may contribute to the demise of neurons in age-related disorders such as Alzheimer's disease [20Davydov V. Hansen L.A. Shackelford D.A. Is DNA repair compromised in Alzheimer's disease?.Neurobiol. Aging. 2003; 24: 953-968Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar]. It will be of particular importance now to determine the influence of both dramatic and subtle variation in the different DNA-damage responses, particularly the SSB repair processing enzymes (Figure 1), as well as environmental factors, such as diet and lifestyle, on the susceptibility of neurons during aging.