J Korean Neurosurg Soc.  2020 Sep;63(5):579-589. 10.3340/jkns.2019.0182.

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

Affiliations
  • 1Institute for Stem Cell & Regenerative Medicine (ISCRM), Veterinary Medical Center and College of Veterinary Medicine, Chungbuk National University, Cheongju, Korea
  • 2Laboratory of Veterinary Embryology and Biotechnology (VETEMBIO), Veterinary Medical Center and College of Veterinary Medicine, Chungbuk National University, Cheongju, Korea
  • 3Department of Neurosurgery, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
  • 4Department of Medical Neuroscience, College of Medicine, Chungbuk National University, Cheongju, Korea
  • 5Department of Neurosurgery, Chungbuk National University Hospital, Cheongju, Korea
  • 6Department of Biochemistry and Medical Research Center, Chungbuk National University, Cheongju, Korea
  • 7Laboratory of Veterinary Pathology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Korea

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.

Keyword

Huntington disease; Adeno-associated virus vector; Huntingtin protein; Neurodegenerative diseases; Gene delivery
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