Pathological mechanisms underlying TDP-43 driven neurodegeneration in FTLD-ALS spectrum disorders.
Pathological mechanisms underlying TDP-43 driven neurodegeneration in FTLD-ALS spectrum disorders.
复制标题
DOI：
10.1093/hmg/ddt349
复制
发表时间：
2013-10-15
影响因子：
3.5
通讯作者：
Van Broeckhoven C
中科院分区：
文献类型：
--
作者：
Janssens J;Van Broeckhoven C
错误折叠的 TAR DNA 结合蛋白 43 (TDP-43) 的聚集是神经退行性过程的一个显着标志，可在多种神经系统疾病中观察到，特别是在大多数诊断为额颞叶变性 (FTLD) 或肌萎缩侧索硬化症 (ALS) 的患者中。通过在 ALS 家族中 TARDBP（编码 TDP-43 的基因）致病性突变的鉴定，提供了与 TDP-43 脑蛋白病的直接因果关系。然而，在与 ALS 和 FTLD 相关的其他几个基因突变的携带者中也观察到了 TDP-43 蛋白病，这表明 TDP-43 在神经退行性疾病中发挥着关键作用。迄今为止，尽管对 TDP-43 的生物学进行了大量研究，但其在正常大脑和神经退行性过程中的功能仍然很大程度上难以捉摸。尽管如此，细胞和动物模型的突破为 ALS 和 FTLD 发病机制提供了宝贵的见解。越来越多的证据将研究重点转向RNA代谢和蛋白质稳态受损的主要作用。与此同时，有毒的 TDP-43 蛋白聚集体促进神经退行性变的概念正在失去可信度。本综述旨在强调和讨论 TDP-43 驱动的病理机制导致 TDP-43 蛋白病中观察到的神经变性的当前知识。基于相关神经系统疾病的复杂性，清楚地了解基本的病理改变对于进一步的治疗干预至关重要。
Aggregation of misfolded TAR DNA-binding protein 43 (TDP-43) is a striking hallmark of neurodegenerative processes that are observed in several neurological disorders, and in particular in most patients diagnosed with frontotemporal lobar degeneration (FTLD) or amyotrophic lateral sclerosis (ALS). A direct causal link with TDP-43 brain proteinopathy was provided by the identification of pathogenic mutations in TARDBP, the gene encoding TDP-43, in ALS families. However, TDP-43 proteinopathy has also been observed in carriers of mutations in several other genes associated with both ALS and FTLD demonstrating a key role for TDP-43 in neurodegeneration. To date, and despite substantial research into the biology of TDP-43, its functioning in normal brain and in neurodegeneration processes remains largely elusive. Nonetheless, breakthroughs using cellular and animal models have provided valuable insights into ALS and FTLD pathogenesis. Accumulating evidence has redirected the research focus towards a major role for impaired RNA metabolism and protein homeostasis. At the same time, the concept that toxic TDP-43 protein aggregates promote neurodegeneration is losing its credibility. This review aims at highlighting and discussing the current knowledge on TDP-43 driven pathomechanisms leading to neurodegeneration as observed in TDP-43 proteinopathies. Based on the complexity of the associated neurological diseases, a clear understanding of the essential pathological modifications will be crucial for further therapeutic interventions.
登录
查看更多内容
影响因子：
16.2
作者：
Ash PE;Bieniek KF;Gendron TF;Caulfield T;Lin WL;Dejesus-Hernandez M;van Blitterswijk MM;Jansen-West K;Paul JW 3rd;Rademakers R;Boylan KB;Dickson DW;Petrucelli L
通讯作者：
Petrucelli L
影响因子：
3.5
作者：
Belzil, Veronique V.;Gendron, Tania F.;Petrucelli, Leonard
通讯作者：
Petrucelli, Leonard
影响因子：
8.8
作者：
Almeida S;Zhang Z;Coppola G;Mao W;Futai K;Karydas A;Geschwind MD;Tartaglia MC;Gao F;Gianni D;Sena-Esteves M;Geschwind DH;Miller BL;Farese RV Jr;Gao FB
通讯作者：
Gao FB
影响因子：
4
作者：
Ayala, Youhna M.;Zago, Paola;Baralle, Francisco E.
通讯作者：
Baralle, Francisco E.
DOI：
10.1073/pnas.1202922109
发表时间：
2012-04-10
影响因子：
11.1
作者：
Bilican, Bilada;Serio, Andrea;Chandran, Siddharthan
通讯作者：
Chandran, Siddharthan