Mutation in senataxin alters the mechanism of R-loop resolution in amyotrophic lateral sclerosis 4.
Mutation in senataxin alters the mechanism of R-loop resolution in amyotrophic lateral sclerosis 4.
复制标题
DOI：
10.1093/brain/awab464
复制
发表时间：
2022-09-14
期刊：
影响因子：
--
通讯作者：
中科院分区：
文献类型：
--
作者：
senataxin（SETX）基因突变导致常染色体显性神经肌肉疾病，肌萎缩性侧索硬化4（ALS 4），其特征在于运动神经元变性、肌肉无力和萎缩。SETX是介导共转录RNA：DNA杂合体（R环）的分解的RNA-DNA解旋酶。R环分解的过程对于包括神经元在内的细胞的正常功能至关重要。ALS 4发病机制的分子基础和R环分解的机制尚不清楚。我们报告说，锌指蛋白ZPR 1结合RNA：DNA杂交，招募SETX到R环上，是R环分辨率的关键。ZPR 1缺陷破坏了含有SETX的R环解析复合物的完整性，并导致整个基因转录过程中R环积累增加。我们发现SETX是ZPR 1的下游靶点，并且ZPR 1的过表达可以挽救SETX缺陷细胞中的R环解析装配，但反之亦然。为了揭示R环分辨率的机制，我们使用两种具有改变的R环分辨率的遗传运动神经元疾病模型来检查SETX-ZPR 1复合物的功能。值得注意的是，慢性低水平的SETX-ZPR 1复合物在R环上导致R环分解活性的降低，从而导致脊髓性肌萎缩症中R环水平的增加。ZPR 1过表达增加了SETX在R环上的募集，减少了R环，并挽救了运动神经元和患者细胞中的脊髓性肌萎缩表型。引人注目的是，SETX与ZPR 1的相互作用在具有杂合SETX（L389 S）突变的ALS 4患者中被破坏。ZPR 1不能募集突变的SETX同源二聚体，但募集了SETX和ZPR 1之间相互作用部分破坏的异源二聚体。有趣的是，SETX-ZPR 1复合物的破坏导致R环解析活性增加，导致ALS 4中的R环减少。ZPR 1水平的调节调节了ALS 4患者细胞中的R环积累并挽救了致病性R环表型。这些发现起源于一个新的概念，“细胞生物学活性（R环分辨率）的相反改变导致不同遗传运动神经元疾病的相似发病机制（神经变性）”。我们建议，ZPR 1与SETX合作，并可能作为一个分子制动器，以调节运动神经元的正常功能至关重要的SETX依赖的R环分辨率活动。senataxin（SETX）基因突变导致ALS 4，一种幼年型ALS。Kannan等人通过显示SETX突变破坏SETX和锌指蛋白ZPR 1之间的相互作用，干扰RNA-DNA杂交体（R环）的解析，提供了对ALS 4发病机制的分子基础的见解。
Mutation in the senataxin (SETX) gene causes an autosomal dominant neuromuscular disorder, amyotrophic lateral sclerosis 4 (ALS4), characterized by degeneration of motor neurons, muscle weakness and atrophy. SETX is an RNA-DNA helicase that mediates resolution of co-transcriptional RNA:DNA hybrids (R-loops). The process of R-loop resolution is essential for the normal functioning of cells, including neurons. The molecular basis of ALS4 pathogenesis and the mechanism of R-loop resolution are unclear. We report that the zinc finger protein ZPR1 binds to RNA:DNA hybrids, recruits SETX onto R-loops and is critical for R-loop resolution. ZPR1 deficiency disrupts the integrity of R-loop resolution complexes containing SETX and causes increased R-loop accumulation throughout gene transcription. We uncover that SETX is a downstream target of ZPR1 and that overexpression of ZPR1 can rescue R-loop resolution complexe assembly in SETX-deficient cells but not vice versa. To uncover the mechanism of R-loop resolution, we examined the function of SETX-ZPR1 complexes using two genetic motor neuron disease models with altered R-loop resolution. Notably, chronic low levels of SETX-ZPR1 complexes onto R-loops result in a decrease of R-loop resolution activity causing an increase in R-loop levels in spinal muscular atrophy. ZPR1 overexpression increases recruitment of SETX onto R-loops, decreases R-loops and rescues the spinal muscular atrophy phenotype in motor neurons and patient cells. Strikingly, interaction of SETX with ZPR1 is disrupted in ALS4 patients that have heterozygous SETX (L389S) mutation. ZPR1 fails to recruit the mutant SETX homodimer but recruits the heterodimer with partially disrupted interaction between SETX and ZPR1. Interestingly, disruption of SETX-ZPR1 complexes causes increase in R-loop resolution activity leading to fewer R-loops in ALS4. Modulation of ZPR1 levels regulates R-loop accumulation and rescues the pathogenic R-loop phenotype in ALS4 patient cells. These findings originate a new concept, ‘opposite alterations in a cell biological activity (R-loop resolution) result in similar pathogenesis (neurodegeneration) in different genetic motor neuron disorders’. We propose that ZPR1 collaborates with SETX and may function as a molecular brake to regulate SETX-dependent R-loop resolution activity critical for the normal functioning of motor neurons. Mutations in the senataxin (SETX) gene cause ALS4, a juvenile form of ALS. Kannan et al. provide insights into the molecular basis of ALS4 pathogenesis by showing that SETX mutations disrupt the interaction between SETX and the zinc finger protein ZPR1, interfering with the resolution of RNA-DNA hybrids (R-loops).
登录
查看更多内容
影响因子：
3.5
作者：
Bhatia V;Herrera-Moyano E;Aguilera A;Gómez-González B
通讯作者：
Gómez-González B
影响因子：
--
作者：
Ahmad S;Bhatia K;Kannan A;Gangwani L
通讯作者：
Gangwani L
影响因子：
3
作者：
Corcia, P.;Couratier, P.;Vourc'h, P.
通讯作者：
Vourc'h, P.
DOI：
10.1007/978-3-319-89689-2_10
发表时间：
2018-01-01
期刊：
RNA METABOLISM IN NEURODEGENERATIVE DISEASES
影响因子：
--
作者：
Bennett, Craig L.;La Spada, Albert R.
通讯作者：
La Spada, Albert R.
影响因子：
16.6
作者：
Cohen S;Puget N;Lin YL;Clouaire T;Aguirrebengoa M;Rocher V;Pasero P;Canitrot Y;Legube G
通讯作者：
Legube G