Atypical TDP-43 protein expression in an ALS pedigree carrying a p.Y374X truncation mutation in TARDBP.
Atypical TDP-43 protein expression in an ALS pedigree carrying a p.Y374X truncation mutation in TARDBP.
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DOI：
10.1111/bpa.13104
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发表时间：
2023-01
期刊：
影响因子：
6.4
通讯作者：
Shaw, Pamela J.
中科院分区：
文献类型：
--
作者：
Cooper-Knock, Johnathan;Julian, Thomas H.;Feneberg, Emily;Highley, J. Robin;Sidra, Maurice;Turner, Martin R.;Talbot, Kevin;Ansorge, Olaf;Allen, Scott P.;Moll, Tobias;Shelkovnikova, Tatyana;Castelli, Lydia;Hautbergue, Guillaume M.;Hewitt, Christopher;Kirby, Janine;Wharton, Stephen B.;Mead, Richard J.;Shaw, Pamela J.
我们描述了一个常染色体显性、多代遗传的肌萎缩侧索硬化症(ALS)家系，其中疾病与TDP-43内的杂合子p.Y374X无义突变共分离。TDP-43定位错误和形成难溶的TDP-43阳性神经元胞质包涵体是95%的ALS患者的标志性病理。1例有中枢神经系统组织的病例神经病理学检查显示，下运动神经元内有典型的TDP-43病理改变，但运动皮质中没有典型的TDP-43阳性包涵体。突变的等位基因在患者成纤维细胞和运动皮质组织中转录和翻译，但与野生型对照相比，总体TDP-43蛋白表达减少。尽管没有TDP-43阳性包涵体，但我们证实运动皮质组织中存在TDP-43剪接功能缺陷。此外，携带突变的运动皮质组织的尿素分级和质谱分析显示非典型的TDP-43蛋白种类，但不是典型的C末端片段。我们得出结论，p.Y374X突变是一种单基因、完全穿透性的ALS的基础。TDP-43的低表达与非典型的TDP-43蛋白种类和缺失的C末端片段相结合，扩展了与TDP-43突变和ALS相关的更广泛的分子表型。未来的工作将需要包括来自该家系的发现，以剖析TDP-43介导的毒性的机制。在这项研究中，Cooper-Knoke等人鉴定了与P.Y374X-TARDBP相关的常染色体显性ALS家系。在患者组织中，作者证实了TDP-43蛋白表达减少，TDP-43异常断裂和TDP-43介导的剪接缺陷。这项工作扩展了与TDP-43突变相关的表型。
We describe an autosomal dominant, multi‐generational, amyotrophic lateral sclerosis (ALS) pedigree in which disease co‐segregates with a heterozygous p.Y374X nonsense mutation within TDP‐43. Mislocalization of TDP‐43 and formation of insoluble TDP‐43‐positive neuronal cytoplasmic inclusions is the hallmark pathology in >95% of ALS patients. Neuropathological examination of the single case for which CNS tissue was available indicated typical TDP‐43 pathology within lower motor neurons, but classical TDP‐43‐positive inclusions were absent from motor cortex. The mutated allele is transcribed and translated in patient fibroblasts and motor cortex tissue, but overall TDP‐43 protein expression is reduced compared to wild‐type controls. Despite absence of TDP‐43‐positive inclusions we confirmed deficient TDP‐43 splicing function within motor cortex tissue. Furthermore, urea fractionation and mass spectrometry of motor cortex tissue carrying the mutation revealed atypical TDP‐43 protein species but not typical C‐terminal fragments. We conclude that the p.Y374X mutation underpins a monogenic, fully penetrant form of ALS. Reduced expression of TDP‐43 combined with atypical TDP‐43 protein species and absent C‐terminal fragments extends the molecular phenotypes associated with TDP‐43 mutations and with ALS more broadly. Future work will need to include the findings from this pedigree in dissecting the mechanisms of TDP‐43‐mediated toxicity. In this study Cooper‐Knock et al identified an autosomal dominant ALS pedigree associated with p.Y374X‐TARDBP. In patient tissue the authors confirmed reduced TDP‐43 protein expression, abnormal TDP‐43 fragmentation and deficient TDP‐43‐mediated splicing. This work extends the phenotypes associated with TDP‐43 mutations.
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影响因子：
4.8
作者：
Theunissen F;Anderton RS;Mastaglia FL;Flynn LL;Winter SJ;James I;Bedlack R;Hodgetts S;Fletcher S;Wilton SD;Laing NG;MacShane M;Needham M;Saunders A;Mackay-Sim A;Melamed Z;Ravits J;Cleveland DW;Akkari PA
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Akkari PA
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通讯作者：
Rouleau, G. A.
影响因子：
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作者：
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通讯作者：
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