Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Neurobiol Aging. 2011 Nov;32(11):2096-9. doi: 10.1016/j.neurobiolaging.2009.11.018. Epub 2009 Dec 23.
Neurodegenerative diseases are often characterized by the presence of aggregates of misfolded proteins. TDP-43 is a major component of these aggregates in amyotrophic lateral sclerosis (ALS), but has also been observed in Alzheimer's (AD) and Parkinson's Diseases (PD). In addition, mutations in the TARDBP gene, encoding TDP-43, have been found to be a significant cause of familial ALS (FALS). All mutations, except for one, have been found in exon 6. To confirm this observation in ALS and to investigate whether TARDBP may play a role in the pathogenesis of AD and PD, we screened for mutations in exon 6 of the TARDBP gene in three cohorts composed of 376 AD, 463 PD (18% familial PD) and 376 ALS patients (50% FALS). We found mutations in ∼ 7% of FALS and ∼0.5% of sporadic ALS (SALS) patients, including two novel mutations, p.N352T and p.G384R. In contrast, we did not find TARDBP mutations in our cohort of AD and PD patients. These results suggest that mutations in TARDBP are not a significant cause of AD and PD.
神经退行性疾病的特征通常是存在错误折叠蛋白质的聚集物。TDP-43 是肌萎缩侧索硬化症（ALS）中这些聚集物的主要成分，但也在阿尔茨海默病（AD）和帕金森病（PD）中观察到。此外，编码 TDP-43 的 TARDBP 基因的突变已被发现是家族性 ALS（FALS）的重要原因。除了一个之外，所有突变都发生在外显子 6 中。为了在 ALS 中证实这一观察结果，并研究 TARDBP 是否可能在 AD 和 PD 的发病机制中发挥作用，我们在由 376 名 AD、463 名 PD（18%为家族性 PD）和 376 名 ALS 患者（50%为 FALS）组成的三个队列中筛选了 TARDBP 基因外显子 6 的突变。我们在约 7%的 FALS 和约 0.5%的散发性 ALS（SALS）患者中发现了突变，包括两个新突变，p.N352T 和 p.G384R。相比之下，我们在 AD 和 PD 患者的队列中未发现 TARDBP 突变。这些结果表明，TARDBP 突变不是 AD 和 PD 的重要原因。
