相关实验视频
Updated: May 28, 2025

10:49
Measuring RAN Peptide Toxicity in C. elegans
Published on: April 30, 2020
6.6K
显著的不匹配修复复合的基因设定了神经元CAG重复扩张率,以驱动HD小鼠的选择性病变
Nan Wang1, Shasha Zhang1, Peter Langfelder1
1Center for Neurobehavioral Genetics, The Jane and Terry Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA, USA; Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
Cell
|February 12, 2025
概括
不匹配修复基因Msh3和Pms1通过减少神经元中有害的CAG重复扩张,显著地拯救了小鼠的亨廷顿病 (HD) 表型. 这一发现为HD提供了新的治疗点.
科学领域:
- 神经科学
- 遗传学
- 分子生物学
背景情况:
- 亨廷顿病 (HD) 的发病包括突变的亨廷丁 (mHtt) 蛋白聚合和神经元功能障碍.
- 不匹配修复 (MMR) 基因是已知的HD修饰剂,但它们在神经元损伤中的具体作用尚未完全理解.
研究的目的:
- 在小鼠模型中研究特定的MMR基因对HD病变的影响.
- 阐明MMR基因影响HD体内CAG重复扩张和神经元表型的机制.
主要方法:
- 在Q140突变亨廷丁 (mHtt) 小鼠中对9个全基因组关联研究 (GWAS) /MMR基因进行基因测试.
- 对表型的分析包括体质CAG重复扩张,转录病变,mHtt聚合和神经/突触/运动功能.
- 评估MMR基因淘汰 (KO) 对这些与HD相关的表型的影响.
主要成果:
- Msh3和Pms1的淘汰强烈地拯救了HD表型,而Msh2和Mlh1则显示了中度的拯救.
- 在中等脊髓神经元 (MSN) 中,MMR基因缺陷显著降低或停止了体质CAG重复扩张的快速速度.
- 通过限制CAG长度,Msh3缺乏可以纠正突触,星细胞和运动缺陷,并防止mHtt聚合.
结论:
- 在易患HD的神经元中,Msh3和Pms1是快速体内CAG重复扩张的关键驱动因素.
- 向Msh3和Pms1可以通过控制重复长度依赖的病原体来缓解HD的治疗策略.
相关概念视频
Mismatch Repair
4.7K
Organisms are capable of detecting and fixing nucleotide mismatches that occur during DNA replication. This sophisticated process requires identifying the new strand and replacing the erroneous bases with correct nucleotides. Mismatch repair is coordinated by many proteins in both prokaryotes and eukaryotes.
The Mutator Protein Family Plays a Key Role in DNA Mismatch Repair
The human genome has more than 3 billion base pairs of DNA per cell. Prior to cell division, that vast amount of genetic...
The Mutator Protein Family Plays a Key Role in DNA Mismatch Repair
The human genome has more than 3 billion base pairs of DNA per cell. Prior to cell division, that vast amount of genetic...
4.7K
Homologous Recombination
50.1K
The basic reaction of homologous recombination (HR) involves two chromatids that contain DNA sequences sharing a significant stretch of identity. One of these sequences uses a strand from another as a template to synthesize DNA in an enzyme-catalyzed reaction. The final product is a novel amalgamation of the two substrates. To ensure an accurate recombination of sequences, HR is restricted to the S and G2 phases of the cell cycle. At these stages, the DNA has been replicated already and the...
50.1K
Nucleotide Excision Repair
3.4K
DNA Distortion and Damage
Cells are regularly exposed to mutagens—factors in the environment that can damage DNA and generate mutations. UV radiation is one of the most common mutagens and is estimated to introduce a significant number of changes in DNA. These include bends or kinks in the structure, which can block DNA replication or transcription. If these errors are not fixed, the damage can cause mutations, which in turn can result in cancer or disease depending on which sequences are...
Cells are regularly exposed to mutagens—factors in the environment that can damage DNA and generate mutations. UV radiation is one of the most common mutagens and is estimated to introduce a significant number of changes in DNA. These include bends or kinks in the structure, which can block DNA replication or transcription. If these errors are not fixed, the damage can cause mutations, which in turn can result in cancer or disease depending on which sequences are...
3.4K
Nucleosome Remodeling
8.9K
Nucleosomes are the basic units of chromatin compaction. Each nucleosome consists of the DNA bound tightly around a histone core, which makes the DNA inaccessible to DNA binding proteins such as DNA polymerase and RNA polymerase. Hence, the fundamental problem is to ensure access to DNA when appropriate, despite the compact and protective chromatin structure.
Nucleosome remodeling complex
Eukaryotic cells have specialized enzymes called ATP-dependent nucleosome remodeling enzymes. These enzymes...
Nucleosome remodeling complex
Eukaryotic cells have specialized enzymes called ATP-dependent nucleosome remodeling enzymes. These enzymes...
8.9K
Exon Recombination
3.5K
The evolution of new genes is critical for speciation. Exon recombination, also known as exon shuffling or domain shuffling, is an important means of new gene formation. It is observed across vertebrates, invertebrates, and in some plants such as potatoes and sunflowers. During exon recombination, exons from the same or different genes recombine and produce new exon-intron combinations, which might evolve into new genes.
Exon shuffling follows “splice frame rules.” Each exon...
Exon shuffling follows “splice frame rules.” Each exon...
3.5K

