TDP-43 loss and ALS-risk SNPs drive mis-splicing and depletion of UNC13A.
TDP-43 loss and ALS-risk SNPs drive mis-splicing and depletion of UNC13A.
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DOI：
10.1038/s41586-022-04436-3
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发表时间：
2022-03
期刊：
影响因子：
64.8
通讯作者：
Fratta P
中科院分区：
文献类型：
--
作者：
Brown AL;Wilkins OG;Keuss MJ;Hill SE;Zanovello M;Lee WC;Bampton A;Lee FCY;Masino L;Qi YA;Bryce-Smith S;Gatt A;Hallegger M;Fagegaltier D;Phatnani H;NYGC ALS Consortium;Newcombe J;Gustavsson EK;Seddighi S;Reyes JF;Coon SL;Ramos D;Schiavo G;Fisher EMC;Raj T;Secrier M;Lashley T;Ule J;Buratti E;Humphrey J;Ward ME;Fratta P
UNC 13 A是突触功能的关键基因，其变异增加了肌萎缩侧索硬化症和额颞叶痴呆的风险，这两种相关的神经退行性疾病由RNA结合蛋白TDP-43的错误定位定义。在这里，我们表明，TDP-43耗尽诱导UNC 13 A中的隐藏外显子的强大包含，导致UNC 13 A蛋白的无义介导的衰变和丢失。两种常见的内含子UNC 13 A多态性与肌萎缩侧索硬化和额颞叶痴呆风险密切相关，与TDP-43结合位点重叠。这些多态性增强了培养细胞以及患有这些疾病的患者的大脑和脊髓中的隐藏外显子包含。我们的研究结果表明，核TDP-43功能丧失与疾病之间存在遗传联系，揭示了UNC 13 A变异加剧TDP-43功能降低的机制。它们还为TDP-43蛋白病提供了有希望的治疗靶点。突触基因UNC 13 A中ALS和FTD的风险变体增加了TDP-43耗竭神经元中UNC 13 A隐性外显子的表达。
Variants of UNC13A, a critical gene for synapse function, increase the risk of amyotrophic lateral sclerosis and frontotemporal dementia, two related neurodegenerative diseases defined by mislocalization of the RNA-binding protein TDP-43. Here we show that TDP-43 depletion induces robust inclusion of a cryptic exon in UNC13A, resulting in nonsense-mediated decay and loss of UNC13A protein. Two common intronic UNC13A polymorphisms strongly associated with amyotrophic lateral sclerosis and frontotemporal dementia risk overlap with TDP-43 binding sites. These polymorphisms potentiate cryptic exon inclusion, both in cultured cells and in brains and spinal cords from patients with these conditions. Our findings, which demonstrate a genetic link between loss of nuclear TDP-43 function and disease, reveal the mechanism by which UNC13A variants exacerbate the effects of decreased TDP-43 function. They further provide a promising therapeutic target for TDP-43 proteinopathies. Risk variants for ALS and FTD in the synaptic gene UNC13A increase the expression of an UNC13A cryptic exon in neurons with TDP-43 depletion.
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影响因子：
2.7
作者：
Humphrey J;Emmett W;Fratta P;Isaacs AM;Plagnol V
通讯作者：
Plagnol V
影响因子：
48
作者：
Langmead, Ben;Salzberg, Steven L.
通讯作者：
Salzberg, Steven L.
影响因子：
14.9
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Frankish A;Diekhans M;Ferreira AM;Johnson R;Jungreis I;Loveland J;Mudge JM;Sisu C;Wright J;Armstrong J;Barnes I;Berry A;Bignell A;Carbonell Sala S;Chrast J;Cunningham F;Di Domenico T;Donaldson S;Fiddes IT;García Girón C;Gonzalez JM;Grego T;Hardy M;Hourlier T;Hunt T;Izuogu OG;Lagarde J;Martin FJ;Martínez L;Mohanan S;Muir P;Navarro FCP;Parker A;Pei B;Pozo F;Ruffier M;Schmitt BM;Stapleton E;Suner MM;Sycheva I;Uszczynska-Ratajczak B;Xu J;Yates A;Zerbino D;Zhang Y;Aken B;Choudhary JS;Gerstein M;Guigó R;Hubbard TJP;Kellis M;Paten B;Reymond A;Tress ML;Flicek P
通讯作者：
Flicek P
DOI：
10.1073/pnas.1507125112
发表时间：
2015-06-09
影响因子：
11.1
作者：
Darmanis S;Sloan SA;Zhang Y;Enge M;Caneda C;Shuer LM;Hayden Gephart MG;Barres BA;Quake SR
通讯作者：
Quake SR
影响因子：
14.9
作者：
Buniello, Annalisa;MacArthur, Jacqueline A. L.;Parkinson, Helen
通讯作者：
Parkinson, Helen