242
Views
0
CrossRef citations to date
0
Altmetric
Review

Animal models of Huntington’s disease and their applicability to novel drug discovery and development

, &
Pages 527-538 | Received 26 Jun 2022, Accepted 06 Apr 2023, Published online: 11 Apr 2023

References

  • Georgiou-Karistianis N, Egan GF, Egan GF. Connectivity-based segmentation of the striatum in Huntington’s disease: vulnerability of motor pathways. Neurobiol Dis. 2011;42(3):475–481.
  • Baig SS, Strong M, Quarrell OW. The global prevalence of Huntington’s disease: a systematic review and discussion. Neurodegener Dis Manag. 2016;6(4):331–343.
  • Ament SA, Pearl JR, Grindeland A, et al. High resolution time-course mapping of early transcriptomic, molecular and cellular phenotypes in Huntington’s disease CAG knock-in mice across multiple genetic backgrounds. Hum Mol Genet. 2017;26(5):913–922. DOI:10.1093/hmg/ddx006
  • Pringsheim T, Wiltshire K, Day L, et al. The incidence and prevalence of Huntington’s disease: a systematic review and meta-analysis. Mov Disord. 2012;27(9):1083–1091. DOI:10.1002/mds.25075
  • Claassen DO, Ayyagari R, Garcia-Horton V, et al. Real-world adherence to tetrabenazine or deutetrabenazine among patients with huntington’s disease: a retrospective database analysis. Neurol Ther. 2022;11(1):435–448. DOI:10.1007/s40120-021-00309-5
  • Maehle A-H. Animal experimentation from antiquity to the end of the eighteenth century: attitudes and arguments. In: Rupke A, editor. Vivisection in historical perspective. London: Croom Helm; 1987. p. 14–47.
  • Davidson M, Lindsey J, Davis J. Requirements and selection of an animal model. Isr J Med Sci. 1987;23(6):551–555.
  • Rand MS. Selection of biomedical animal models. In: Conn PM, editor. Sourcebook of models for biomedical research. Totowa, NJ: Humana Press; 2008. p. 9–15.
  • Singh VK, Seed TM. How necessary are animal models for modern drug discovery? Expert Opin Drug Discov. 2021;16(12):1391–1397.
  • Pouladi MA, Morton AJ, Hayden MR. Choosing an animal model for the study of Huntington’s disease. Nat Rev Neurosci. 2013;14(10):708–721.
  • Freires IA, Sardi J, de Castro RD, et al. Alternative animal and non-animal models for drug discovery and development: bonus or burden? 11. Pharm Res. 2017;34(4):681–686. DOI:10.1007/s11095-016-2069-z
  • Neri C. Value of invertebrate genetics and biology to develop neuroprotective and preventive medicine in Huntington’s disease. In: Lo DC, Hughes RE, editor. Neurobiology of Huntington’s disease: applications to drug discovery. Boca Raton: CRC Press/Taylor & Francis; 2011. p. 1–39.
  • Hobert O. Neurogenesis in the nematode Caenorhabditis elegans. WormBook: the online review of C. Elegans Biology. 2018;1–24. DOI:10.1895/wormbook.1.161.1
  • Parker JA, Metzler M, Georgiou J, et al. Huntingtin-interacting protein 1 influences worm and mouse presynaptic function and protects Caenorhabditis elegans neurons against mutant polyglutamine toxicity. J Neurosci. 2007;27(41):11056–11064. DOI:10.1523/JNEUROSCI.1941-07.2007
  • Rudich P, Lamitina T. Models and mechanisms of repeat expansion disorders: a worm’s eye view. J Genet. 2018;97(3):665–677.
  • Ma L, Zhao Y, Chen Y, et al. Caenorhabditis elegans as a model system for target identification and drug screening against neurodegenerative diseases. Eur J Pharmacol. 2018;819:169–180.
  • Cordeiro LM, Soares MV, da Silva AF, et al. Neuroprotective effects of rutin on ASH neurons in Caenorhabditis elegans model of Huntington’s disease. Nutr Neurosci. 2021;25(11):2288–2301.
  • Bicca Obetine Baptista F, Arantes LP, Machado ML, et al. Diphenyl diselenide protects a Caenorhabditis elegans model for Huntington’s disease by activation of the antioxidant pathway and a decrease in protein aggregation. Metallomics. 2020;12(7):1142–1158. DOI:10.1039/d0mt00074d
  • Boasquívis PF, Silva GMM, Paiva FA, et al. Guarana (Paullinia cupana) extract protects Caenorhabditis elegans models for Alzheimer disease and Huntington disease through activation of antioxidant and protein degradation pathways. Oxid Med Cell Longev. 2018;16: 1–16. 9241308. DOI:10.1155/2018/9241308
  • Zhang J, Shi R, Li H, et al. Antioxidant and neuroprotective effects of Dictyophora indusiata polysaccharide in Caenorhabditis elegans. J Ethnopharmacol. 2016;192:413–422.
  • Zhang S, Feany MB, Saraswati S, et al. Inactivation of Drosophila Huntingtin affects long-term adult functioning and the pathogenesis of a Huntington’s disease model. Dis Model Mech. 2009;2(5–6):247–266. DOI:10.1242/dmm.000653
  • Donnelly KM, Pearce MM. Monitoring cell-to-cell transmission of prion-like protein aggregates in Drosophila melanogaster. JoVe. 2018;133:e56906. DOI:10.3791/56906
  • Lewis EA, Smith GA. Using Drosophila models of Huntington’s disease as a translatable tool. J Neurosci Methods. 2016;265:89–98.
  • Lin Y-H, Maaroufi HO, Ibrahim E, et al. Expression of human mutant huntingtin protein in Drosophila hemocytes impairs immune responses. Front Immunol. 2019;10:2405.
  • Smith MR, Syed A, Lukacsovich T, et al. A potent and selective sirtuin 1 inhibitor alleviates pathology in multiple animal and cell models of Huntington’s disease. Hum Mol Genet. 2014;23(11):2995–3007. DOI:10.1093/hmg/ddu010
  • Casale AM, Liguori F, Ansaloni F, et al. Transposable element activation promotes neurodegeneration in a Drosophila model of Huntington’s disease. Iscience. 2022;25(1):103702. DOI:10.1016/j.isci.2021.103702
  • Arabit JG, Elhaj R, Schriner SE, et al. Rhodiola rosea improves lifespan, locomotion, and neurodegeneration in a Drosophila melanogaster model of Huntington’s disease. BioMed Res Int. 2018;2018:1–8.
  • Xiao L, Li H, Zhang J, et al. Salidroside protects Caenorhabditis elegans neurons from polyglutamine-mediated toxicity by reducing oxidative stress. Molecules. 2014;19(6):7757–7769. DOI:10.3390/molecules19067757
  • Delfino L, Mason RP, Kyriacou CP, et al. Rab8 promotes mutant HTT aggregation, reduces neurodegeneration, and ameliorates behavioural alterations in a Drosophila model of Huntington’s disease. J Huntington’s Dis. 2020;9(3):253–263. DOI:10.3233/JHD-200411
  • Das S, Rajanikant G. Huntington disease: can a zebrafish trail leave more than a ripple? Neurosci Biobehav Rev. 2014;45:258–261.
  • Vaz RL, Outeiro TF, Ferreira JJ. Zebrafish as an animal model for drug discovery in Parkinson’s disease and other movement disorders: a systematic review. Front Neurol. 2018;9:347.
  • Veldman MB, Rios-Galdamez Y, X-H L, et al. The N17 domain mitigates nuclear toxicity in a novel zebrafish Huntington’s disease model. Mol Neurodegener. 2015;10(1):1–16. DOI:10.1186/s13024-015-0063-2
  • Diekmann H, Anichtchik O, Fleming A, et al. Decreased BDNF levels are a major contributor to the embryonic phenotype of huntingtin knockdown zebrafish. J Neurosci. 2009;29(5):1343–1349. DOI:10.1523/JNEUROSCI.6039-08.2009
  • Sager JJ, Bai Q, Burton EA. Transgenic zebrafish models of neurodegenerative diseases. Brain Struct Funct. 2010;214(2–3):285–302.
  • Xi Y, Noble S, Ekker M. Modeling neurodegeneration in zebrafish. Curr Neurol Neurosci Rep. 2011;11(3):274–282.
  • Gama Sosa MA, De Gasperi R, Elder GA. Modeling human neurodegenerative diseases in transgenic systems. Hum Genet. 2012;131(4):535–563.
  • Conforti P, Zuccato C, Gaudenzi G, et al. Binding of the repressor complex REST‐mSIN 3b by small molecules restores neuronal gene transcription in Huntington’s disease models. J Neurochem. 2013;127(1):22–35. DOI:10.1111/jnc.12348
  • Kumar V, Singh A. Targeting N17 domain as a potential therapeutic target for the treatment of Huntington disease: an opinion. Excli J. 2021;20:1086.
  • Kumar P, Kalonia H, Kumar A. Huntington’s disease: pathogenesis to animal models. Pharmacol Rep. 2010;62(1):1–14.
  • Barré-Sinoussi F, Montagutelli X. Animal models are essential to biological research: issues and perspectives. Future Sci OA. 2015;1(4):1–3. DOI:10.4155/fso.15.63
  • Hervás-Corpión I, Guiretti D, Alcaraz-Iborra M, et al. Early alteration of epigenetic-related transcription in Huntington’s disease mouse models. Sci Rep. 2018;8(1):1–14. DOI:10.1038/s41598-018-28185-4
  • Dabrowska M, Ciolak A, Kozlowska E, et al. Generation of new isogenic models of Huntington’s disease using CRISPR-Cas9 technology. Int J Mol Sci. 2020;21(5):1854. DOI:10.3390/ijms21051854
  • Ekman FK, Ojala DS, Adil MM, et al. CRISPR-Cas9-mediated genome editing increases lifespan and improves motor deficits in a Huntington’s disease mouse model. Mol Ther Nucleic Acids. 2019;17:829–839.
  • Suelves N, Miguez A, López-Benito S, et al. Early downregulation of p75NTR by genetic and pharmacological approaches delays the onset of motor deficits and striatal dysfunction in Huntington’s disease mice. Mol Neurobiol. 2019;56(2):935–953. DOI:10.1007/s12035-018-1126-5
  • Lu AT, Narayan P, Grant MJ, et al. DNA methylation study of Huntington’s disease and motor progression in patients and in animal models. Nat Commun. 2020;11(1):1–15. DOI:10.1038/s41467-020-18255-5
  • Agrawal S, Fox JH. Novel proteomic changes in brain mitochondria provide insights into mitochondrial dysfunction in mouse models of Huntington’s disease. Mitochondrion. 2019;47:318–329.
  • Kurat S, Heinrich P, Molnar-Kasza A, et al. Homozygosity of BACHD rats not only causes strong behavioral deficits in young female rats but also a reduced breeding success. Brain Res. 2021;1761:147396.
  • Southwell AL, Skotte NH, Kordasiewicz HB, et al. In vivo evaluation of candidate allele-specific mutant huntingtin gene silencing antisense oligonucleotides. Mol Ther. 2014;22(12):2093–2106. DOI:10.1038/mt.2014.153
  • Datson NA, González-Barriga A, Kourkouta E, et al. The expanded CAG repeat in the huntingtin gene as target for therapeutic RNA modulation throughout the HD mouse brain. PLoS ONE. 2017;12:e0171127.
  • Stanek LM, Sardi SP, Mastis B, et al. Silencing mutant huntingtin by adeno-associated virus-mediated RNA interference ameliorates disease manifestations in the YAC128 mouse model of Huntington’s disease. Hum Gene Ther. 2014;25(5):461–474. DOI:10.1089/hum.2013.200
  • Suganya SN, Sumathi T. Effect of rutin against a mitochondrial toxin, 3-nitropropionicacid induced biochemical, behavioral and histological alterations-a pilot study on Huntington’s disease model in rats. Metab Brain Dis. 2017;32(2):471–481.
  • Mishra J, Kumar A. Improvement of mitochondrial NAD+/FAD±linked state-3 respiration by caffeine attenuates quinolinic acid induced motor impairment in rats: implications in Huntington’s disease. Pharmacol Rep. 2014;66(6):1148–1155.
  • Underwood BR, Imarisio S, Fleming A, et al. Antioxidants can inhibit basal autophagy and enhance neurodegeneration in models of polyglutamine disease. Hum Mol Genet. 2010;19(17):3413–3429. DOI:10.1093/hmg/ddq253
  • Yuan C, Zheng L, Zhao Y. Protective effect of 3-n-butylphthalide against intrastriatal injection of malonic acid-induced neurotoxicity and biochemical alteration in rats. Biomed Pharmacother. 2022;155:113664.
  • Kumar P, Kumar A. Protective effect of rivastigmine against 3-nitropropionic acid-induced Huntington’s disease like symptoms: possible behavioural, biochemical and cellular alterations. Eur J Pharmacol. 2009;615(1–3):91–101. DOI:10.1016/j.ejphar.2009.04.058
  • Navrotskaya V, Oxenkrug G. Effect of kynurenic acid on development and aging in wild type and vermilion mutants of Drosophila melanogaster. Pharmacol Drug Dev Ther. 2016;1(1):1–7.
  • Kumar P, Padi SSV, Naidu PS, et al. Effect of resveratrol on 3-nitropropionic acid-induced biochemical and behavioural changes: possible neuroprotective mechanisms. Behav Pharmacol. 2006;17(5–6):485–492. DOI:10.1097/00008877-200609000-00014
  • Kalonia H, Kumar P, Kumar A. Targeting oxidative stress attenuates malonic acid induced Huntington like behavioral and mitochondrial alterations in rats. Eur J Pharmacol. 2010;634(1–3):46–52.
  • Ramachandran S, Thangarajan S. Thymoquinone loaded solid lipid nanoparticles counteracts 3-Nitropropionic acid induced motor impairments and neuroinflammation in rat model of Huntington’s disease. Metab Brain Dis. 2018;33(5):1459–1470.
  • Menze ET, Esmat A, Tadros MG, et al. Genistein improves 3-NPA-induced memory impairment in ovariectomized rats: impact of its antioxidant, anti-inflammatory and acetylcholinesterase modulatory properties. PLoS ONE. 2015;10(2):e0117223. DOI:10.1371/journal.pone.0117223
  • Mustafa AM, Rabie MA, Zaki HF, et al. Inhibition of brain GTP cyclohydrolase i attenuates 3-Nitropropionic acid-induced striatal toxicity: involvement of mas receptor/PI3k/Akt/CREB/BDNF axis. Front Pharmacol. 2021;12. DOI:10.3389/fphar.2021.740966
  • Gopinath K, Sudhandiran G. Naringin modulates oxidative stress and inflammation in 3-nitropropionic acid-induced neurodegeneration through the activation of nuclear factor-erythroid 2-related factor-2 signalling pathway. Neurosci J. 2012;227:134–143.
  • Bansal PK, Deshmukh R. Animal models of neurological disorders: principle and working procedure for animal models of neurological disorders. Springer Nature Singapore. 2018;1:1–343.
  • Chidambaram SB, Vijayan R, Sekar S, et al. Simultaneous blockade of NMDA receptors and PARP-1 activity synergistically alleviate immunoexcitotoxicity and bioenergetics in 3-nitropropionic acid intoxicated mice: evidences from memantine and 3-aminobenzamide interventions. Eur J Pharmacol. 2017;803:148–158.
  • Coyle JT, Schwarcz R. Lesion of striatal neurons with kainic acid provides a model for Huntington’s chorea. Nature. 1976;263(5574):244–246. DOI:10.1038/263244a0
  • Jamwal S, Kumar P. Spermidine ameliorates 3-nitropropionic acid (3-NP)-induced striatal toxicity: possible role of oxidative stress, neuroinflammation, and neurotransmitters. Physiol Behav. 2016;155:180–187.
  • Bondulich MK, Fan Y, Song Y, et al. Ablation of kynurenine 3-monooxygenase rescues plasma inflammatory cytokine levels in the R6/2 mouse model of Huntington’s disease. Sci Rep. 2021;11(1):1–18. DOI:10.1038/s41598-021-84858-7
  • Spronck EA, Vallès A, Lampen MH, et al. Intrastriatal administration of AAV5-miHTT in non-human primates and rats is well tolerated and results in miHTT transgene expression in key areas of Huntington disease pathology. Brain Sci. 2021;11(2):129. DOI:10.3390/brainsci11020129
  • Clemens LE, Weber JJ, Wlodkowski TT, et al. Olesoxime suppresses calpain activation and mutant huntingtin fragmentation in the BACHD rat. Brain. 2015;138(12):3632–3653. DOI:10.1093/brain/awv290
  • Singh S, Jamwal S, Kumar P. Piperine enhances the protective effect of curcumin against 3-NP induced neurotoxicity: possible neurotransmitters modulation mechanism. Neurochem Res. 2015;40(8):1758–1766.
  • Torabi A, Joneidi M, Mohammadzadeh I, et al. The effect of 3-nitropropionic acid on behavioral dysfunction, neuron loss and gliosis in the brain of adult male rats: the case of prefrontal cortex, hippocampus and the cerebellum. Toxicon. 2020;183:44–50.
  • Torres‐cruz FM, Mendoza E, Vivar‐cortés IC, et al. Do BDNF and NT‐4/5 exert synergistic or occlusive effects on corticostriatal transmission in a male mouse model of Huntington’s disease? J Neuro Res. 2019;97:1665–1677.
  • Stepanova P, Srinivasan V, Lindholm D, et al. Cerebral dopamine neurotrophic factor (CDNF) protects against quinolinic acid-induced toxicity in in vitro and in vivo models of Huntington’s disease. Sci Rep. 2020;10(1):1–12. DOI:10.1038/s41598-020-75439-1
  • Kovalenko M, Milnerwood A, Giordano J, et al. Htt Q111/+ Huntington’s disease knock-in mice exhibit brain region-specific morphological changes and synaptic dysfunction. J Huntington’s Dis. 2018;7(1):17–33. DOI:10.3233/JHD-170282
  • Morton AJ, Howland DS. Large genetic animal models of Huntington’s disease. J Huntington’s Dis. 2013;2(1):3–19. DOI:10.3233/JHD-130050
  • Handley R, Reid SJ, Patassini S, et al. Metabolic disruption identified in the Huntington’s disease transgenic sheep model. Sci Rep. 2016;6(1):1–11. DOI:10.1038/srep20681
  • Morton A. Large-brained animal models of huntington’s disease: sheep. In: Precious S, Rosser A Dunnett S, editors. Huntington’s disease. methods in molecular biology. Vol. 1780. New York (NY): Humana Press; 2018. p. 221–239.
  • Handley RR, Reid SJ, Brauning R, et al. Brain urea increase is an early Huntington’s disease pathogenic event observed in a prodromal transgenic sheep model and HD cases. Proc Natl Acad Sci. 2017;114(52):E11293–11302. DOI:10.1073/pnas.1711243115
  • Laowtammathron C, Cheng EC, Cheng P-H, et al. Monkey hybrid stem cells develop cellular features of Huntington’s disease. BMC Cell Biol. 2010;11(1):1–12. DOI:10.1186/1471-2121-11-12
  • Snyder BR, Chan AW. Progress in developing transgenic monkey model for Huntington’s disease. J Neural Transm. 2018;125(3):401–417.
  • Yan S, Tu Z, Liu Z, et al. A Huntingtin knockin pig model recapitulates features of selective neurodegeneration in Huntington’s disease. Cell. 2018;173(4):989–1002. e13. DOI:10.1016/j.cell.2018.03.005
  • Yang D, Wang C-E, Zhao B, et al. Expression of Huntington’s disease protein results in apoptotic neurons in the brains of cloned transgenic pigs. Hum Mol Genet. 2010;19(20):3983–3994. DOI:10.1093/hmg/ddq313
  • Klonarakis M, De Vos M, Woo E, et al. The three sisters of fate: genetics, pathophysiology and outcomes of animal models of neurodegenerative diseases. Neuro sci Biobehav Rev. 2022;135:104541.
  • Wang C-E, Tydlacka S, Orr AL, et al. Accumulation of N-terminal mutant huntingtin in mouse and monkey models implicated as a pathogenic mechanism in Huntington’s disease. Hum Mol Genet. 2008;17(17):2738–2751. DOI:10.1093/hmg/ddn175
  • Baxa M, Levinska B, Skrivankova M, et al. Longitudinal study revealing motor, cognitive and behavioral decline in a transgenic minipig model of Huntington’s disease. Dis Model Mech. 2020;13:dmm041293.
  • Sams-Dodd F. Strategies to optimize the validity of disease models in the drug discovery process. Drug Discov Today. 2006;11(7–8):355–363.
  • Denayer T, Stöhr T, Van Roy M. Animal models in translational medicine: validation and prediction. New Horiz Transl. 2014;2(1):5–11. DOI:10.1016/j.nhtm.2014.08.001
  • Belzung C, Lemoine M. Criteria of validity for animal models of psychiatric disorders: focus on anxiety disorders and depression. Biol Mood Anxiety Disord. 2011;1(1):1–14.
  • Geyer MA, Markou A. Animal models of psychiatric disorders. In: Floyd E, and Kupfer David J, editors. Psychopharmacology: the fourth generation of progress. New York: Raven Press; 1995. p. 787–798.
  • McGonigle P, Ruggeri B. Animal models of human disease: challenges in enabling translation. Biochem Pharmacol. 2014;87(1):162–171.
  • van Wamelen DJ, Aziz NA, Roos RA, et al. Hypothalamic alterations in Huntington’s disease patients: comparison with genetic rodent models. J Neuroendocrinol. 2014;26(11):761–775. DOI:10.1111/jne.12190
  • Wiprich MT, Zanandrea R, Altenhofen S, et al. Influence of 3-nitropropionic acid on physiological and behavioral responses in zebrafish larvae and adults. Comp Biochem Physiol C Toxicol Pharmacol. 2020;234:108772.
  • Dash D, Mestre TA. Therapeutic update on huntington’s disease: symptomatic treatments and emerging disease-modifying therapies. Neurotherapeutics. 2020;17(4):1645–1659.
  • Kumar A, Kumar V, Singh K, et al. Therapeutic advances for Huntington’s disease. Brain Sci. 2020;10(1):43. DOI:10.3390/brainsci10010043
  • Ryskamp D, Wu J, Geva M, et al. The sigma-1 receptor mediates the beneficial effects of pridopidine in a mouse model of Huntington disease. Neurobiol Dis. 2017;97:46–59.
  • Zhemkov V, Geva M, Hayden MR, et al. Sigma-1 receptor (S1R) Interaction with cholesterol: mechanisms of S1R activation and its role in neurodegenerative diseases. Int J Mol Sci. 2021;22(8):4082. DOI:10.3390/ijms22084082
  • Asla MM, Nawar AA, Abdelsalam A, et al. The efficacy and safety of pridopidine on treatment of patients with huntington’s disease: a systematic review and meta-analysis. Mov Disord Clin Pract. 2022;9(1):20–30. DOI:10.1002/mdc3.13357
  • Chen S, Liang T, Xue T, et al. Pridopidine for the improvement of motor function in patients with huntington’s disease: a systematic review and meta-analysis of randomized controlled trials. Front Neurol. 2021;12:658123.
  • Kim A, Lalonde K, Truesdell A, et al. New avenues for the treatment of Huntington’s disease. Int J Mol Sci. 2021;22(16):8363. DOI:10.3390/ijms22168363
  • Ségalat L. Invertebrate animal models of diseases as screening tools in drug discovery. ACS Chem Biol. 2007;2(4):231–236.
  • Travessa AM, Rodrigues FB, Mestre TA, et al. Fifteen years of clinical trials in Huntington’s disease: a very low clinical drug development success rate. J Huntington’s Dis. 2017;6(2):157–163. DOI:10.3233/JHD-170245
  • Braz BY, Wennagel D, Ratié L, et al. Treating early postnatal circuit defect delays Huntington’s disease onset and pathology in mice. Science. 2022;377(6613):eabq5011. DOI:10.1126/science.abq5011
  • Rodríguez-Urgellés E, Rodríguez-Navarro I, Ballasch I, et al. Postnatal foxp2 regulates early psychiatric-like phenotypes and associated molecular alterations in the R6/1 transgenic mouse model of Huntington’s disease. Neurobiol Dis. 2022;173:105854.
  • L Burrows E, J Hannan A. Towards environmental construct validity in animal models of CNS disorders: optimizing translation of preclinical studies. CNS Neurol Disord - Drug Targ. 2013;12(5):587–592. DOI:10.2174/1871527311312050007

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.