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Huntingdon disease (HD)-targeted proteins and their coding genes and use

A chorea and protein technology, applied in the field of genetic engineering, can solve problems such as lack of detail, copper ion distribution status, copper ion balance regulation status is not clear, etc.

Inactive Publication Date: 2013-07-31
TSINGHUA UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006]Although the proteins involved in copper ion transport in the human brain have been identified including Ctr1, Atox1, CCS, ScoI / II, ATP7A, ATP7B, they are different in the human brain The distribution of copper ions in cells and the regulation of copper ion balance are still unclear.
[0007]Although some in vitro experiments show that copper ions may have a certain relationship with the pathogenesis of HD, there has been no more detailed and convincing in vivo evidence to prove

Method used

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  • Huntingdon disease (HD)-targeted proteins and their coding genes and use
  • Huntingdon disease (HD)-targeted proteins and their coding genes and use
  • Huntingdon disease (HD)-targeted proteins and their coding genes and use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0533] Example 1: Drosophila Ctr1B and dmATP7 genes affect copper balance in the brain

[0534] 1. Acquisition of Ctr1B RNAi, dmATP7 OE and dmATP7 RNAi transgenic flies and detection of transcription level

[0535] The Ctr1B RNAi transgenic flies used in the experiment were purchased from fly stocks of National Institute of Genetics (NIG), the dmATP7 OE transgenic flies were purchased from Bloomington Drosophila Stock Center, and the dmATP7 RNAi transgenic flies were purchased from Vienna Drosophila RNAi Center.

[0536] In order to detect the abundance of target genes in the brain of different genotypes of fruit flies, transgenic fruit flies strains were crossed with Elav-Gal4 transgenic fruit flies strains, and the offspring of Elav> 10 days after emergence were selected. Ctr1B RNAi, Elav> dmATP7 OE,, Elav> dmATP7 RNAi and Elav> + / +Transgenic Drosophila, each genotype dissected 20 Drosophila brains, 3 replicates, total RNA extraction and semi-quantitative reverse transcription PCR (...

Embodiment 2

[0541] Example 2: Specific regulation of the expression levels of Ctr1B and dmATP7 in the Drosophila nervous system can significantly affect brain HTT protein deposition

[0542] In this experiment, with the help of an HD fruit fly model expressing htt exon1 polyQQ103-EGFP, green fluorescent protein was used to mark the accumulation of htt exon1 polyQ. The specific operation is as follows: dissecting the Drosophila brain, fixing it in 4% paraformaldehyde for 20 minutes, then washing it three times with PBS, translucent in glycerol for 30 minutes, and mounting in glycerin. The film was observed with Zeiss SM 510 confocal laser microscope, and the data was analyzed with LSM510 analysis software. The results show that( Figure 4 ), silencing Ctr1 or overexpression of dmATP7 will reduce or even eliminate the accumulation of htt exon1 polyQ, while inhibiting the expression of dmATP7 will increase the accumulation of htt exon1 polyQ.

Embodiment 3

[0543] Example 3 The specific regulation of the expression levels of Ctr1B and dmATP7 in the Drosophila nervous system can significantly affect the loss of pigment in the eye of HD Drosophila and the degeneration of the optic nerve rod in the eye

[0544] The effects of Ctr1B RNAi and specific expression of dmATP7 and dmATP7 RNAi on the eye pigment loss and the degeneration of the optic nerve sensor rod in the eyes of HD Drosophila were studied through resin semi-thin sectioning and staining of the eyes of different genotypes of fruit flies. HD Drosophila eye pigment loss and the degeneration of the optic nerve rod in the eye are caused by the death of the nerve inside the eye, because the eye pigment loss in Drosophila and the degeneration of the optic nerve rod in the eye can be used as the severity of Drosophila nerve degeneration symbols of. The specific operations are as follows:

[0545] 1. Observe the loss of eye pigment in Drosophila under the asanasscope

[0546] Collect f...

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Abstract

The invention relates to the field of gene engineering and especially relates to Huntingdon disease (HD)-targeted proteins and their coding genes and use. The HD-targeted genes provided by the invention comprise Ctrl, ATP7A and ATP7B, and through gene silencing interference of Ctrl or overexpression of ATP7A and ATP7B, HD patient symptoms are obviously relieved or HD occurrence is delayed. According to the invention, the human HD-targeted proteins have amino acid sequences shown in the formulas of SEQ ID No.5, SEQ ID No.6, SEQ ID No.7, SEQ ID No.8 and SEQ ID No.9. The genes have nucleotide sequences shown in the formulas of SEQ ID No.10, SEQ ID No.11, SEQ ID No.12, SEQ ID No.13 and SEQ ID No.14. Through gene silencing or gene overexpression, the targeted genes can be used for improving HD patient athletic ability, prolonging a HD patient life, and relieving or preventing cut huntingtin (htt) deposition in the brain and htt deposition-caused nerve degeneration. The invention provides a novel treatment approach and key target positions for HD.

Description

technical field [0001] The present invention relates to the field of genetic engineering, specifically, the present invention relates to a target protein of Huntington's disease (Huntingdon Disease, HD), its encoding gene and application. Background technique [0002] Huntington's disease (HD), also known as chronic progressive chorea, is one of the major neurodegenerative diseases currently affecting human health. This is a late-onset neurodegenerative genetic disease, mainly in middle-aged and elderly people, occasionally in children and adolescents, both men and women can be affected, the onset is insidious, and it is slowly progressive. It is clinically manifested as a "triad", including dance Similar involuntary movements, mental disorders and progressive dementia, the average survival period is 10-20 years. Since this disease mostly occurs after middle age, and there is no effective treatment, the disease can only be allowed to progress and eventually lead to death. ...

Claims

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Application Information

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IPC IPC(8): C07K14/435C12N15/12C12N15/63A61K38/17A61K48/00A61P25/14
Inventor 周兵肖桂然范强旺
Owner TSINGHUA UNIV
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