Abstract
Huntington’s disease (HD) is an autosomal-dominant inherited neurodegenerative disorder characterized by motor, psychiatric and cognitive symptoms. HD is caused by an expansion of CAG repeats in the huntingtin (HTT) gene in various areas of the brain including striatum. There are few suitable animal models to study the pathogenesis of HD and validate therapeutic strategies. Recombinant adeno-associated viral (AAV) vectors successfully transfer foreign genes to the brain of adult mammalians. In this article, we report a novel mouse model of HD generated by bilateral intrastriatal injection of AAV vector serotype DJ (AAV-DJ) containing N171-82Q mutant HTT (82Q) and N171-18Q wild type HTT (18Q; sham). The AAV-DJ-82Q model displayed motor dysfunctions in pole and rotarod tests beginning 4 weeks after viral infection in juvenile mice (8 weeks after birth). They showed behaviors reflecting neurodegeneration. They also showed increased apoptosis, robust glial activation and upregulated representative inflammatory cytokines (tumor necrosis factor-alpha (TNF-α) and interleukin (IL)-6), mediators (cyclooxygenase-2 and inducible nitric oxide synthase) and signaling pathways (nuclear factor kappa B and signal transducer and activator of transcription 3 (STAT3)) in the striatum at 10 weeks after viral infection (14 weeks after birth) via successful transfection of mutant HTT into neurons, microglia, and astrocytes in the striatum. However, little evidence of any of these events was found in mice infected with the AAV-DJ-18Q expressing construct. Intrastriatal injection of AAV-DJ-82Q might be useful as a novel in vivo model to investigate the biology of truncated N-terminal fragment (N171) in the striatum and to explore the efficacy of therapeutic strategies for HD.
Highlights
In the pole test, beginning at week 4 after associated viral (AAV)-DJ-82Q mutant HTT (82Q) injection (8 weeks after birth), the average descent time to the bottom of the pole was increased (5.7 ± 0.3 and 6.3 ± 0.2 s in the 0.62 × 1012 genome copies/ml (GC/ml) and 1.23 × 1012 GC/ml groups, respectively) 8 weeks after injection (12 weeks after birth) compared to the sham group (4.3 ± 0.5 s at 8 weeks after injection) and AAV vector serotype DJ (AAV-DJ)-18Q wild type HTT (18Q) (4.0 ± 0.3 s at 8 weeks after injection) groups (Figure 1A)
The average latency to fall was reduced since week 4 after the AAV-DJ-82Q injection (282.9 ± 2.3 and 280.3 ± 1.7 s in the 0.62 × 1012 GC/ml and 1.23 × 1012 GC/ml groups, respectively, 8 weeks after injection) compared with the sham group (289.5 ± 1.9 s, 8 weeks after injection) and AAV-DJ-18Q (290.5 ± 1.3 s, 8 weeks after injection; Figure 1B)
At the end of experiment, all mice were alive. These results suggest that AAV-DJ-82Q-injection can successfully induce neurological impairment
Summary
Huntington’s disease (HD) is an inherited progressive neurodegenerative disorder characterized by involuntary abnormal movements (chorea), cognitive decline and emotional as well as psychiatric disturbances (Damiano et al, 2010; Jacobsen et al, 2011; Gil-Mohapel et al, 2014). The expansion encodes a prolonged polyglutamine sequence that results in conformational change of the HTT protein and induces the formation of intranuclear inclusions of mutant HTT in various areas of the brain. This mutation leads to neuronal loss and neuronal degeneration, most prominently in the striatum (Damiano et al, 2010; Jacobsen et al, 2011; Gil-Mohapel et al, 2014).
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
