title: Significantly differential diffusion of neuropathological aggregates in the brain of transgenic mice carrying N-terminal mutant huntingtin fused with green fluorescent protein.
abstract: Huntington's disease (HD) is a genetically neurodegenerative disease, affecting the central nervous system and leading to mental and motor dysfunctions. To date, there is no cure for HD; as a result, HD patients gradually suffer devastating symptoms, such as chorea, weight loss, depression and mood swings, until death. According to previous studies, the exon 1 region of the huntingtin (HTT) gene with expanded CAG trinucleotide repeats plays a critical role in causing HD. In vitro studies using exon 1 of HTT fused with green fluorescent protein (GFP) gene have facilitated discovering several mechanisms of HD. However, whether this chimera construct exerts similar functions in vivo is still not clear. Here, we report the generation of transgenic mice carrying GFP fused with mutant HTT exon 1 containing 84 CAG trinucleotide repeats, and the evaluation of phenotypes via molecular, neuropathological and behavioral analyses. Results show that these transgenic mice not only displayed neuropathological characteristics, observed either by green fluorescent signals or by immunohistochemical staining, but also progressively developed pathological and behavioral symptoms of HD. Most interestingly, these transgenic mice showed significantly differential expression levels of nuclear aggregates between cortex and striatum regions, highly mimicking selective expression of mutant HTT in HD patients. To the best of our knowledge, this is the first report showing different nuclear diffusion profiling in mouse models with transgenic mice carrying the exon 1 region of mutant HTT. Our model will be beneficial for tracing the expression of mutant HTT and accelerating the understanding of selective pathological progression in HD.
authors.affiliation: Department of Physiology, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan.
authors.forename: Pei-Hsun
authors.initials: PH
authors.lastname: Cheng
authors.forename: Chia-Ling
authors.initials: CL
authors.lastname: Li
authors.forename: Lu-Shiun
authors.initials: LS
authors.lastname: Her
authors.forename: Yu-Fan
authors.initials: YF
authors.lastname: Chang
authors.forename: Anthony W S
authors.initials: AW
authors.lastname: Chan
authors.forename: Chuan-Mu
authors.initials: CM
authors.lastname: Chen
authors.forename: Shang-Hsun
authors.initials: SH
authors.lastname: Yang
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D005091:Exons; D005838:Genotype; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000523:psychology; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity; D053580:Muscle Strength; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D018911:Trinucleotide Repeats
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D011993:Recombinant Fusion Proteins; D049452:Green Fluorescent Proteins