Journal of Korean Neurosurgical Society

The Korean Neurosurgical Society (대한신경외과학회)
권호 표지
DOI QR코드

DOI QR Code

An Optimization of AAV-82Q-Delivered Rat Model of Huntington's Disease

  • So, Kyoung-Ha (Institute for Stem Cell & Regenerative Medicine (ISCRM), Veterinary Medical Center and College of Veterinary Medicine, Chungbuk National University) ;
  • Choi, Jai Ho (Department of Neurosurgery, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea) ;
  • Islam, Jaisan (Department of Medical Neuroscience, College of Medicine, Chungbuk National University) ;
  • KC, Elina (Department of Medical Neuroscience, College of Medicine, Chungbuk National University) ;
  • Moon, Hyeong Cheol (Department of Medical Neuroscience, College of Medicine, Chungbuk National University) ;
  • Won, So Yoon (Department of Biochemistry and Medical Research Center, Chungbuk National University) ;
  • Kim, Hyong Kyu (Department of Biochemistry and Medical Research Center, Chungbuk National University) ;
  • Kim, Soochong (Laboratory of Veterinary Pathology, College of Veterinary Medicine, Chungbuk National University) ;
  • Hyun, Sang-Hwan (Institute for Stem Cell & Regenerative Medicine (ISCRM), Veterinary Medical Center and College of Veterinary Medicine, Chungbuk National University) ;
  • Park, Young Seok (Institute for Stem Cell & Regenerative Medicine (ISCRM), Veterinary Medical Center and College of Veterinary Medicine, Chungbuk National University)
  • Received : 2019.08.27
  • Accepted : 2019.11.25
  • Published : 2020.09.01
Download PDF
⟨ Previous Next ⟩

Abstract

Objective : No optimum genetic rat Huntington model both neuropathological using an adeno-associated virus (AAV-2) vector vector has been reported to date. We investigated whether direct infection of an AAV2 encoding a fragment of mutant huntingtin (AV2-82Q) into the rat striatum was useful for optimizing the Huntington rat model. Methods : We prepared ten unilateral models by injecting AAV2-82Q into the right striatum, as well as ten bilateral models. In each group, five rats were assigned to either the 2×1012 genome copies (GC)/mL of AAV2-82Q (×1, low dose) or 2×1013 GC/mL of AAV2-82Q (×10, high dose) injection model. Ten unilateral and ten bilateral models injected with AAV-empty were also prepared as control groups. We performed cylinder and stepping tests 2, 4, 6, and 8 weeks after injection, tested EM48 positive mutant huntingtin aggregates. Results : The high dose of unilateral and bilateral AAV2-82Q model showed a greater decrease in performance on the stepping and cylinder tests. We also observed more prominent EM48-positive mutant huntingtin aggregates in the medium spiny neurons of the high dose of AAV2-82Q injected group. Conclusion : Based on the results from the present study, high dose of AAV2-82Q is the optimum titer for establishing a Huntington rat model. Delivery of high dose of human AAV2-82Q resulted in the manifestation of Huntington behaviors and optimum expression of the huntingtin protein in vivo.

Keywords

References

  1. Alexander GE, Crutcher MD : Preparation for movement: neural representations of intended direction in three motor areas of the monkey. J Neurophysiol 64 : 133-150, 1990 https://doi.org/10.1152/jn.1990.64.1.133
  2. Cattoglio C, Facchini G, Sartori D, Antonelli A, Miccio A, Cassani B, et al. : Hot spots of retroviral integration in human CD34+ hematopoietic cells. Blood 110 : 1770-1778, 2007
  3. Ceccarelli I, Fiengo P, Remelli R, Miragliotta V, Rossini L, Biotti I, et al. : Recombinant Adeno Associated Viral (AAV) vector type 9 delivery of Ex1-Q138-mutant huntingtin in the rat striatum as a short-time model for in vivo studies in drug discovery. Neurobiol Dis 86 : 41-51, 2016 https://doi.org/10.1016/j.nbd.2015.11.019
  4. Davies SW, Turmaine M, Cozens BA, DiFiglia M, Sharp AH, Ross CA, et al. : Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the HD mutation. Cell 90 : 537-548, 1997 https://doi.org/10.1016/S0092-8674(00)80513-9
  5. Daya S, Berns KI : Gene therapy using adeno-associated virus vectors. Clin Microbiol Rev 21 : 583-593, 2008 https://doi.org/10.1128/CMR.00008-08
  6. de Almeida LP, Ross CA, Zala D, Aebischer P, Deglon N : Lentiviralmediated delivery of mutant huntingtin in the striatum of rats induces a selective neuropathology modulated by polyglutamine repeat size, huntingtin expression levels, and protein length. J Neurosci 22 : 3473-3483, 2002 https://doi.org/10.1523/jneurosci.22-09-03473.2002
  7. DiFiglia M, Sapp E, Chase KO, Davies SW, Bates GP, Vonsattel JP, et al. : Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain. Science 277 : 1990-1993, 1997 https://doi.org/10.1126/science.277.5334.1990
  8. Foster AC, Whetsell WO Jr, Bird ED, Schwarcz R : Quinolinic acid phosphoribosyltransferase in human and rat brain: activity in Huntington's disease and in quinolinate-lesioned rat striatum. Brain Res 336 : 207-214, 1985 https://doi.org/10.1016/0006-8993(85)90647-X
  9. Hodgson JG, Agopyan N, Gutekunst CA, Leavitt BR, LePiane F, Singaraja R, et al. : A YAC mouse model for Huntington's disease with full-length mutant huntingtin, cytoplasmic toxicity, and selective striatal neurodegeneration. Neuron 23 : 181-192, 1999 https://doi.org/10.1016/S0896-6273(00)80764-3
  10. Hoth KF, Paulsen JS, Moser DJ, Tranel D, Clark LA, Bechara A : Patients with Huntington's disease have impaired awareness of cognitive, emotional, and functional abilities. J Clin Exp Neuropsychol 29 : 365-376, 2007 https://doi.org/10.1080/13803390600718958
  11. Hua Y, Schallert T, Keep RF, Wu J, Hoff JT, Xi G : Behavioral tests after intracerebral hemorrhage in the rat. Stroke 33 : 2478-2484, 2002 https://doi.org/10.1161/01.str.0000032302.91894.0f
  12. Jang M, Lee SE, Cho IH : Adeno-associated viral vector serotype DJmediated overexpression of N171-82Q-mutant huntingtin in the striatum of juvenile mice is a new model for Huntington's disease. Front Cell Neurosci 12 : 157, 2018 https://doi.org/10.3389/fncel.2018.00157
  13. Kim M : Brain Transplantation for Huntington Disease. Tissue Eng Regen Med 2 : 322-326, 2005
  14. MacDonald ME, Ambrose CM, Duyao MP, Myers RH, Lin C, Srinidhi L et al. : A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. The Huntington's Disease Collaborative Research Group. Cell 72 : 971-983, 1993 https://doi.org/10.1016/0092-8674(93)90585-e
  15. Mangiarini L, Sathasivam K, Mahal A, Mott R, Seller M, Bates GP : Instability of highly expanded CAG repeats in mice transgenic for the Huntington's disease mutation. Nat Genet 15 : 197-200, 1997 https://doi.org/10.1038/ng0297-197
  16. Mangiarini L, Sathasivam K, Seller M, Cozens B, Harper A, Hetherington C, et al. : Exon 1 of the HD gene with an expanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice. Cell 87 : 493-506, 1996 https://doi.org/10.1016/S0092-8674(00)81369-0
  17. Marini B, Kertesz-Farkas A, Ali H, Lucic B, Lisek K, Manganaro L, et al. : Nuclear architecture dictates HIV-1 integration site selection. Nature 521 : 227-231, 2015 https://doi.org/10.1038/nature14226
  18. Nussbaum RL, McInnes RR, Willard HF : Thompson & Thompson genetics in medicine. Philadelphia : Elsevier Health Sciences, 2015
  19. Olsson M, Nikkhah G, Bentlage C, Bjorklund A : Forelimb akinesia in the rat Parkinson model: differential effects of dopamine agonists and nigral transplants as assessed by a new stepping test. J Neurosci 15(5 Pt 2) : 3863-3875, 1995 https://doi.org/10.1523/JNEUROSCI.15-05-03863.1995
  20. Palfi S, Brouillet E, Jarraya B, Bloch J, Jan C, Shin M, et al. : Expression of mutated huntingtin fragment in the putamen is sufficient to produce abnormal movement in non-human primates. Mol Ther 15 : 1444-1451, 2007 https://doi.org/10.1038/sj.mt.6300185
  21. Radua J, van den Heuvel OA, Surguladze S, Mataix-Cols D : Metaanalytical comparison of voxel-based morphometry studies in obsessivecompulsive disorder vs other anxiety disorders. Arch Gen Psychiatry 67 : 701-711, 2010 https://doi.org/10.1001/archgenpsychiatry.2010.70
  22. Ramaswamy S, McBride JL, Kordower JH : Animal models of Huntington's disease. ILAR J 48 : 356-373, 2007 https://doi.org/10.1093/ilar.48.4.356
  23. Reddy PH, Charles V, Williams M, Miller G, Whetsell WO Jr, Tagle DA : Transgenic mice expressing mutated full-length HD cDNA: a paradigm for locomotor changes and selective neuronal loss in Huntington's disease. Philos Trans R Soc Lond B Biol Sci 354 : 1035-1045, 1999 https://doi.org/10.1098/rstb.1999.0456
  24. Reddy PH, Williams M, Charles V, Garrett L, Pike-Buchanan L, Whetsell WO Jr, et al. : Behavioural abnormalities and selective neuronal loss in HD transgenic mice expressing mutated full-length HD cDNA. Nat Genet 20 : 198-202, 1998 https://doi.org/10.1038/2510
  25. Reddy PH, Williams M, Tagle DA : Recent advances in understanding the pathogenesis of Huntington's disease. Trends Neurosci 22 : 248-255, 1999 https://doi.org/10.1016/S0166-2236(99)01415-0
  26. Regulier E, Trottier Y, Perrin V, Aebischer P, Deglon N : Early and reversible neuropathology induced by tetracycline-regulated lentiviral overexpression of mutant huntingtin in rat striatum. Hum Mol Genet 12 : 2827-2836, 2003 https://doi.org/10.1093/hmg/ddg305
  27. Sanberg PR, Calderon SF, Giordano M, Tew JM, Norman AB : The quinolinic acid model of Huntington's disease: locomotor abnormalities. Exp Neurol 105 : 45-53, 1989 https://doi.org/10.1016/0014-4886(89)90170-2
  28. Schilling G, Becher MW, Sharp AH, Jinnah HA, Duan K, Kotzuk JA, et al. : Intranuclear inclusions and neuritic aggregates in transgenic mice expressing a mutant N-terminal fragment of huntingtin. Hum Mol Genet 8 : 397-407, 1999 https://doi.org/10.1093/hmg/8.3.397
  29. Senut MC, Suhr ST, Kaspar B, Gage FH : Intraneuronal aggregate formation and cell death after viral expression of expanded polyglutamine tracts in the adult rat brain. J Neurosci 20 : 219-229, 2000 https://doi.org/10.1523/jneurosci.20-01-00219.2000
  30. Shelbourne PF, Killeen N, Hevner RF, Johnston HM, Tecott L, Lewandoski M, et al. : A Huntington's disease CAG expansion at the murine Hdh locus is unstable and associated with behavioural abnormalities in mice. Hum Mol Genet 8 : 763-774, 1999 https://doi.org/10.1093/hmg/8.5.763
  31. Slow EJ, van Raamsdonk J, Rogers D, Coleman SH, Graham RK, Deng Y, et al. : Selective striatal neuronal loss in a YAC128 mouse model of Huntington disease. Hum Mol Genet 12 : 1555-1567, 2003 https://doi.org/10.1093/hmg/ddg169
  32. Stack EC, Ferrante RJ : Huntington's disease: progress and potential in the field. Expert Opin Investig Drugs 16 : 1933-1953, 2007 https://doi.org/10.1517/13543784.16.12.1933
  33. Stack EC, Kubilus JK, Smith K, Cormier K, Signore SJD, Guelin E, et al. : Chronology of behavioral symptoms and neuropathological sequela in R6/2 Huntington's disease transgenic mice. J Comp Neurol 490 : 354-370, 2005 https://doi.org/10.1002/cne.20680
  34. Vorisek I, Syka M, Vargova L : Brain diffusivity and structural changes in the R6/2 mouse model of huntington disease. J Neurosci Res 95 : 1474-1484, 2017 https://doi.org/10.1002/jnr.23965
  35. Wheeler VC, Auerbach W, White JK, Srinidhi J, Auerbach A, Ryan A, et al. : Length-dependent gametic CAG repeat instability in the Huntington's disease knock-in mouse. Hum Mol Genet 8 : 115-122, 1999 https://doi.org/10.1093/hmg/8.1.115
  36. White JK, Auerbach W, Duyao MP, Vonsattel JP, Gusella JF, Joyner AL, et al. : Huntingtin is required for neurogenesis and is not impaired by the Huntington's disease CAG expansion. Nat Genet 17 : 404-410, 1997 https://doi.org/10.1038/ng1297-404

Cited by

  1. Transplantation of human embryonic stem cells alleviates motor dysfunction in AAV2-Htt171-82Q transfected rat model of Huntington’s disease vol.12, pp.1, 2021, https://doi.org/10.1186/s13287-021-02653-7