Abstract：
:Huntington's disease (HD) is a progressive neurodegenerative disorder caused by an expanded CAG repeat within the huntingtin (HTT) gene. The Q140 and HdhQ150 knock-in HD mouse models were generated such that HdhQ150 mice have an expanded CAG repeat inserted into the mouse Htt gene, whereas in the Q140s, mouse exon 1 Htt was replaced with a mutated version of human exon 1. By standardizing mouse strain background, breeding to homozygosity and employing sensitive behavioral tests, we demonstrate that the onset of behavioral phenotypes occurs earlier in the Q140 than the HdhQ150 knock-in mouse models and that huntingtin (HTT) aggregation appears earlier in the striata of Q140 mice. We have previously found that the incomplete splicing of mutant HTT from exon 1 to exon 2 results in the production of a small polyadenylated transcript that encodes the highly pathogenic mutant HTT exon 1 protein. In this report, we have identified a functional consequence of the sequence differences between these two models at the RNA level, in that the level of incomplete splicing, and of the mutant exon 1 HTT protein, are greater in the brains of Q140 mice. While differences in the human and mouse exon 1 HTT proteins (e.g., proline rich sequences) could also contribute to the phenotypic differences, our data indicate that the incomplete splicing of HTT and approaches to lower the levels of the exon 1 HTT transcript should be pursued as therapeutic targets.
journal_name
J Neurosci Resjournal_title
Journal of neuroscience researchauthors
Franich NR,Hickey MA,Zhu C,Osborne GF,Ali N,Chu T,Bove NH,Lemesre V,Lerner RP,Zeitlin SO,Howland D,Neueder A,Landles C,Bates GP,Chesselet MFdoi
10.1002/jnr.24493subject
Has Abstractpub_date
2019-12-01 00:00:00pages
1590-1605issue
12eissn
0360-4012issn
1097-4547journal_volume
97pub_type
杂志文章abstract：:A series of AMPA [(R,S)-alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid] analogues were evaluated for activity at homomeric, heteromeric, and chimeric rat GluR1(o) and GluR3(o) receptors expressed in Xenopus oocytes, using the two-electrode voltage clamp technique. The formation of heteromeric receptor compl...
journal_title：Journal of neuroscience research
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abstract：:A high density of opioid receptor-like 1 (ORL1) receptor (also referred to as NOP receptor) is found in limbic areas and in regions containing monoamines, which are implicated in emotional activity and physiopathology of depression and anxiety. We aimed at defining precisely the localization of ORL1 receptors in dorsa...
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journal_title：Journal of neuroscience research
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journal_title：Journal of neuroscience research
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