Overview Of Pharmacology And New Treatment Approaches For Neurological Disorders Associated With Xeroderma Pigmentosum
Abstract
The term "xeroderma pigmentosum" (XP) refers to a collection of uncommon disorders that are primarily defined by nucleotide excision repair (NER) dysfunction, increasing the susceptibility of those afflicted to UV light. A small percentage of XP patients—between 25 and 30 percent—have neurological symptoms such ataxia, mental decline, and sensorineural deafness. While the primary etiology of XP is known to be faulty DNA repair, there is mounting evidence that mitochondrial pathology may also be present. Although it seems to be a result of malfunctioning NER, this could accelerate the neurodegenerative process in these individuals. The majority of the pharmacological therapies for XP that are currently available focus on the disease's skin symptoms. In this review, we discuss how new treatments could be created using our existing understanding of the pathophysiology of XP help combat the symptoms of the nervous system. Furthermore, we turned our attention to potential novel pathways that target mitochondrial pathology because XP is associated with both neurodegeneration and malignancy.
References
Alexander SPH, Fabbro D, Kelly E, Marrion NV, Peters JA, Faccenda Eet al. (2017). The Concise Guide to PHARMACOLOGY 2017/18:Enzymes. Br J Pharmacol 174: S272–S359.
Anttinen A, Koulu L, Nikoskelainen E, Portin R, Kurki T, ErkinjunttiM et al. (2008). Neurological symptoms and natural course ofxeroderma pigmentosum. Brain 131: 1979–1989.
Arbault S, Sojic N, Bruce D, Amatore C, Sarasin A, Vuillaume M(2004). Oxidative stress in cancer prone xeroderma pigmentosumfibroblasts. Real-time and single cell monitoring of superoxide andnitric oxide production with microelectrodes. Carcinogenesis 25:509–515
Arczewska KD, Tomazella GG, Lindvall JM, Kassahun H, Maglioni S,Torgovnick A et al. (2013). Active transcriptomic and proteomicreprogramming in the C. elegans nucleotide excision repair mutantXPA-1. Nucleic Acids Res 41: 5368–5381.
Arnold JJ, Smidansky ED, Moustafa IM, Cameron CE (2012). Humanmitochondrial RNA polymerase: structure-function, mechanism andinhibition. Biochim Biophys Acta 1819: 948–960.
Barrientos A, Fontanesi F, Diaz F (2009). Evaluation of themitochondrial respiratory chain and oxidative phosphorylationsystem using polarography and spectrophotometric enzyme assays.Curr Protoc Hum Genet Chapter 19, Unit19.Black JO (2016). Xeroderma pigmentosum. Head Neck Pathol 10:139–144.
Boesch P, Weber-Lotfi F, Ibrahim N, Tarasenko V, Cosset A, Paulus Fet al. (2011). DNA repair in organelles: Pathways, organization,regulation, relevance in disease and aging. Biochim Biophys Acta1813: 186–200.
Bootsma D, Hoeijmakers JH (1991). The genetic basis of xerodermapigmentosum. Ann Genet 34: 143–150.
Bowden NA, Beveridge NJ, Ashton KA, Baines KJ, Scott RJ (2015).Understanding xeroderma pigmentosum complementation groupsusing gene expression profiling after UV-light exposure. Int J Mol Sci16: 15985–15996.
Bradford PT, Goldstein AM, Tamura D, Khan SG, Ueda T, Boyle J et al.(2011). Cancer and neurologic degeneration in xerodermapigmentosum: long term follow-up characterises the role of DNArepair. J Med Genet 48: 168–176.
Brennan-Minnella AM, Arron ST, Chou KM, Cunningham E, CleaverJE (2016). Sources and consequences of oxidative damage frommitochondria and neurotransmitter signaling. Environ Mol Mutagen57: 322–330.
Bohr V, Anson RM, Mazur S, Dianov G (1998). Oxidative DNAdamage processing and changes with aging. Toxicol Lett 102-103:47–52.
Brooks PJ (2008). The 8,50-cyclopurine-20-deoxynucleosides:candidate neurodegenerative DNA lesions in xerodermapigmentosum, and unique probes of transcription and nucleotideexcision repair. DNA Repair (Amst) 7: 1168–1179.
Brooks PJ (2017). The cyclopurine deoxynucleosides: DNA repair,biological effects, mechanistic insights, and unanswered questions.Free Radic Biol Med 107: 90–100.
Brooks BP, Thompson AH, Bishop RJ, Clayton JA, Chan CC, Tsilou ETet al. (2013). Ocular manifestations of xeroderma pigmentosum:long-term follow-up highlights the role of DNA repair in protectionfrom sun damage. Ophthalmology 120: 1324–1336.
Brooks PJ, Wise DS, Berry DA, Kosmoski JV, Smerdon MJ, Somers RLet al. (2000). The oxidative DNA lesion 8,50-(S)-cyclo-20-deoxyadenosine is repaired by the nucleotide excision repairpathway and blocks gene expression in mammalian cells. J Biol Chem275: 22355–22362.
Bove J, Martinez-Vicente M, Vila M (2011). Fightingneurodegeneration with rapamycin: mechanistic insights. Nat RevNeurosci 12: 437–452.
Chretien D, Rustin P (2003). Mitochondrial oxidativephosphorylation: pitfalls and tips in measuring and interpretingenzyme activities. J Inherit Metab Dis 26: 189–198.
Cleaver JE, Brennan-Minnella AM, Swanson RA, Fong KW, Chen J,Chou KM et al. (2014). Mitochondrial reactive oxygen species arescavenged by Cockayne syndrome B protein in human fibroblastswithout nuclear DNA damage. Proc Natl Acad Sci U SA 111:13487–13492.
Clements PM, Breslin C, Deeks ED, Byrd PJ, Ju L, Bieganowski P et al.(2004). The ataxia-oculomotor apraxia 1 gene product has a roledistinct from ATM and interacts with the DNA strand break repairproteins XRCC1 and XRCC4. DNA Repair (Amst) 3: 1493–1502.
Cooke MS, Evans MD, Dizdaroglu M, Lunec J (2003). Oxidative DNAdamage: mechanisms, mutation, and disease. FASEB J 17: 1195–1214.
Dello RC, Lisi L, Feinstein DL, Navarra P (2013). mTOR kinase, a keyplayer in the regulation of glial functions: relevance for the therapy ofmultiple sclerosis. Glia 61: 301–311.
Dean C, Dunning FM, Liu H, Bomba-Warczak E, Martens H, Bharat Vet al. (2012). Axonal and dendritic synaptotagmin isoforms revealedby a pHluorin-syt functional screen. Mol Biol Cell 23: 1715–1727.
DiGiovanna JJ, Kraemer KH (2012). Shining a light on xerodermapigmentosum. J Invest Dermatol 132: 785–796.
DiMauro S, Schon EA (2003). Mitochondrial respiratory-chaindiseases. N Engl J Med 348: 2656–2668.
Droge W (2002). Free radicals in the physiological control of cellfunction. Physiol Rev 82: 47–95.
Duncan AJ, Heales SJ (2005). Nitric oxide and neurological disorders.Mol Aspects Med 26: 67–96.
El-Khamisy SF, Saifi GM, Weinfeld M, Johansson F, Helleday T, LupskiJR et al. (2005). Defective DNA single-strand break repair inspinocerebellar ataxia with axonal neuropathy-1. Nature 434:108–113.
Fang EF, Scheibye-Knudsen M, Brace LE, Kassahun H, SenGupta T,Nilsen H et al. (2014). Defective mitophagy in XPA via PARP-1hyperactivation and NAD(+)/SIRT1 reduction. Cell 157: 882–896.
Fassihi H, Sethi M, Fawcett H, Wing J, Chandler N, Mohammed S et al.(2016). Deep phenotyping of 89 xeroderma pigmentosum patientsreveals unexpected heterogeneity dependent on the precisemolecular defect. Proc Natl Acad Sci U S A 113: E1236–E1245.
Frechet M, Warrick E, Vioux C, Chevallier O, Spatz A, Benhamou Set al. (2008). Overexpression of matrix metalloproteinase 1 in dermalfibroblasts from DNA repair-deficient/cancer-prone xerodermapigmentosum group C patients. Oncogene 27: 5223–5232.
Gilmore EC (2014). DNA repair abnormalities leading to ataxia:shared neurological phenotypes and risk factors. Neurogenetics 15:217–228.
Harding SD, Sharman JL, Faccenda E, Southan C, Pawson AJ, Ireland Set al. (2018). The IUPHAR/BPS Guide to PHARMACOLOGY in 2018:updates and expansion to encompass the new guide toIMMUNOPHARMACOLOGY. Nucl Acids Res 46: D1091–D1106.
Hargreaves IP (2014). Coenzyme Q10 as a therapy for mitochondrialdisease. Int J Biochem Cell Biol 49: 105–111.
Hayashi M (2009). Oxidative stress in developmental brain disorders.Neuropathology 29: 1–8.
Hirai Y, Kodama Y, Moriwaki S, Noda A, Cullings HM, Macphee DGet al. (2006). Heterozygous individuals bearing a founder mutation inthe XPA DNA repair gene comprise nearly 1% of the Japanesepopulation. Mutat Res 601: 171–178.
Jezek P, Hlavata L (2005). Mitochondria in homeostasis of reactiveoxygen species in cell, tissues, and organism. Int J Biochem Cell Biol37: 2478–2503
Kleijer WJ, Laugel V, Berneburg M, Nardo T, Fawcett H, Gratchev Aet al. (2008). Incidence of DNA repair deficiency disorders in westernEurope: Xeroderma pigmentosum, Cockayne syndrome andtrichothiodystrophy. DNA Repair (Amst) 7: 744–750.
Koopman WJ, Nijtmans LG, Dieteren CE, Roestenberg P, Valsecchi F,Smeitink JA et al. (2010). Mammalian mitochondrial complex I:biogenesis, regulation, and reactive oxygen species generation.Antioxid Redox Signal 12: 1431–1470.
Kowaltowski AJ, Vercesi AE (1999). Mitochondrial damage inducedby conditions of oxidative stress. Free Radic Biol Med 26: 463–471.
Kraemer KH, Patronas NJ, Schiffmann R, Brooks BP, Tamura D,DiGiovanna JJ (2007). Xeroderma pigmentosum,trichothiodystrophy and Cockayne syndrome: a complex genotype-phenotype relationship. Neuroscience 145: 1388–1396.
Kulms D, Zeise E, Poppelmann B, Schwarz T (2002). DNA damage,death receptor activation and reactive oxygen species contribute toultraviolet radiation-induced apoptosis in an essential andindependent way. Oncogene 21: 5844–5851.
Kuraoka, I. Bender, A. Romieu, J. Cadet, R.D. Wood, T. (2000).Removal of oxygen free-radical-induced 50,8-purinecyclodeoxynucleosides from DNA by the nucleotide excision-repairpathway in human cells. Proc Natl Acad Sci USA, 3832–3837.
Lambert WC, Lambert MW (2015). Development of effective skincancer treatment and prevention in xeroderma pigmentosum.Photochem Photobiol 91: 475–483.
Le Ber I, Dubourg O, Benoist JF, Jardel C, Mochel F, Koenig M et al.(2007). Muscle coenzyme Q10 deficiencies in ataxia with oculomotorapraxia 1. Neurology 68: 295–297.
Lee MY, Hong S, Kim N, Shin KS, Kang SJ (2015). Tricyclicantidepressants amitriptyline and desipramine inducedneurotoxicity associated with Parkinson’s disease. Mol Cells 38:734–740.
Lehmann AR, Kirk-Bell S, Arlett CF, Paterson MC, Lohman PH, deWeerd-Kastelein EA et al. (1975). Xeroderma pigmentosum cells withnormal levels of excision repair have a defect in DNA synthesis afterUV-irradiation. Proc Natl Acad Sci U S A 72: 219–223.
Lehmann AR, McGibbon D, Stefanini M (2011). Xerodermapigmentosum. Orphanet J Rare Dis 6: 70.Malhotra AK, Gupta S, Khaitan BK, Verma KK (2008). Multiple basalcell carcinomas in xeroderma pigmentosum treated with imiquimod5% cream. Pediatr Dermatol 25: 488–491.
Masutani C, Kusumoto R, Yamada A, Dohmae N, Yokoi M, Yuasa Met al. (1999). The XPV (xeroderma pigmentosum variant) geneencodes human DNA polymerase eta. Nature 399: 700–704.
Mizushima N, Komatsu M (2011). Autophagy: renovation of cells andtissues. Cell 147: 728–741.
Moriwaki S, Kanda F, Hayashi M, Yamashita D, Sakai Y, Nishigori C(2017). Xeroderma pigmentosum clinical practice guidelines.J Dermatol 44: 1087–1096.
Muller FL, Song W, Jang YC, Liu Y, Sabia M, Richardson A et al. (2007).Denervation-induced skeletal muscle atrophy is associated withincreased mitochondrial ROS production. Am J Physiol Regul IntegrComp Physiol 293: R1159–R1168.
Naik SM, Shenoy AM, Nanjundappa A, Halkud R, Chavan P, SidappaK et al. (2013). Cutaneous malignancies in xeroderma pigmentosum:earlier management improves survival. Indian J Otolaryngol HeadNeck Surg 65: 162–167.
Natale V, Raquer H (2017). Xeroderma pigmentosum-Cockaynesyndrome complex. Orphanet J Rare Dis 12: 65.
Niedernhofer LJ (2008). Tissue-specific accelerated aging innucleotide excision repair deficiency. Mech Ageing Dev 129:408–415.
Niedernhofer LJ, Bohr VA, Sander M, Kraemer KH (2011). Xerodermapigmentosum and other diseases of human premature aging andDNA repair: molecules to patients. Mech Ageing Dev 132: 340–347.
Nishigori C, Miyachi Y, Imamura S, Takebe H (1989). Reducedsuperoxide dismutase activity in xeroderma pigmentosumfibroblasts. J Invest Dermatol 93: 506–510.
Osenbroch PØ, Auk-Emblem P, Halsne R, Strand J, Forstrøm RJ, vander Pluijm I et al. (2009). Accumulation of mitochondrial DNAdamage and bioenergetic dysfunction in CSB defective cells. FEBS J276: 2811–2821.
Parlanti E, Pietraforte D, Iorio E, Visentin S, De Nuccio C, Zijno A et al.(2015). An altered redox balance and increased genetic instabilitycharacterize primary fibroblasts derived from xerodermapigmentosum group A patients. Mutat Res 782: 34–43.
Pascucci B, D’Errico M, Parlanti E, Giovannini S, Dogliotti E (2011).Role of nucleotide excision repair proteins in oxidative DNA damagerepair: an updating. Biochemistry (Mosc) 76: 4–15.
Plun-Favreau H, Lewis PA, Hardy J, Martins LM, Wood NW (2010).Cancer and neurodegeneration: between the devil and the deep bluesea. PLoS Genet 6: e1001257.Rass U, Ahel I, West SC (2007). Defective DNA repair andneurodegenerative disease. Cell 130: 991–1004.
Rapin I, Weidenheim K, Lindenbaum Y, Rosenbaum P, Merchant SN,Krishna S et al. (2006). Cockayne syndrome in adults: review withclinical and pathologic study of a new case. J Child Neurol 21:991–1006.
Rothe M, Werner D, Thielmann HW (1993). Enhanced expression ofmitochondrial genes in xeroderma pigmentosum fibroblast strainsfrom various complementation groups. J Cancer Res Clin Oncol 119:675–684.
Scheibye-Knudsen M, Ramamoorthy M, Sykora P, Maynard S, Lin PC,Minor RK et al. (2012). Cockayne syndrome group B protein preventsthe accumulation of damaged mitochondria by promotingmitochondrial autophagy. J Exp Med 209: 855–869.
Scheibye-Knudsen M, Scheibye-Alsing K, Canugovi C, Croteau DL,Bohr VA (2013). A novel diagnostic tool reveals mitochondrialpathology in human diseases and aging. Aging (Albany NY) 5:192–208.
Sethi M, Lehmann AR, Fawcett H, Stefanini M, Jaspers N, Mullard Ket al. (2013). Patients with xeroderma pigmentosumcomplementation groups C, E and V do not have abnormal sunburnreactions. Br J Dermatol 169: 1279–1287.
Singh AK, Kashyap MP, Tripathi VK, Singh S, Garg G, Rizvi SI (2017).Neuroprotection through rapamycin-induced activation ofautophagy and PI3K/Akt1/mTOR/CREB signaling against amyloid-beta-induced oxidative stress, synaptic/neurotransmissiondysfunction, and neurodegeneration in adult rats. Mol Neurobiol 54:5815–5828.
R Abeti et al.4300 British Journal of Pharmacology (2019) 176 4293–4301.
Valko M, Leibfritz D, Moncol J, Cronin MT, Mazur M, Telser J (2007).Free radicals and antioxidants in normal physiological functions andhuman disease. Int J Biochem Cell Biol 39: 44–84.
Vuillaume M, Daya-Grosjean L, Vincens P, Pennetier JL, Tarroux P,Baret A et al. (1992). Striking differences in cellular catalase activitybetween two DNA repair-deficient diseases: xeroderma pigmentosumand trichothiodystrophy. Carcinogenesis 13: 321–328.
Wang Y, Jones-Tabah J, Chakravarty P, Stewart A, Muotri A, LaposaRR et al. (2016). Pharmacological bypass of Cockayne syndrome Bfunction in neuronal differentiation. Cell Rep 14: 2554–2561.
Wang Y, Chakravarty P, Ranes M, Kelly G, Brooks PJ, Neilan E et al.(2014). Dysregulation of gene expression as a cause of Cockaynesyndrome neurological disease. Proc Natl Acad Sci U S A 111:14454–14459.
Wilson BT, Stark Z, Sutton RE, Danda S, Ekbote AV, Elsayed SM et al.(2016). The Cockayne Syndrome Natural History (CoSyNH) study:clinical findings in 102 individuals and recommendations for care.Genet Med 18: 483–493.
Tamura D, DiGiovanna JJ, Khan SG, Kraemer KH (2014). Living withxeroderma pigmentosum: comprehensive photoprotection forhighly photosensitive patients. Photodermatol PhotoimmunolPhotomed 30: 146–152.
Tanaka J, Nagai T, Okada S (1998). Serum concentration of coenzymeQ in xeroderma pigmentosum. Rinsho Shinkeigaku 38: 57–59.
Wilson DM III, Bohr VA (2007). The mechanics of base excisionrepair, and its relationship to aging and disease. DNA Repair (Amst) 6:544–559.
Yang JQ, Chen XY, Engle MY, Wang JY (2015). Multiple facial basalcell carcinomas in xeroderma pigmentosum treated with topicalimiquimod 5% cream. Dermatol Ther 28: 243–247.
Yarosh D, Klein J, O’Connor A, Hawk J, Rafal E, Wolf P (2001). Effectof topically applied T4 endonuclease V in liposomes on skin cancer inxeroderma pigmentosum: a randomised study. XerodermaPigmentosum Study Group. Lancet 357: 926–929.
Yoshihara M, Montana ES (2004). The synaptotagmins: calciumsensors for vesicular trafficking. Neuroscientist 10: 566–574.
Potential therapeutics on XP neurological symptoms4301British Journal of Pharmacology (2019) 176 4293–4301.