Instituto de Investigación Interdisciplinaria, Vicerrectoría Académica, Universidad de Talca, Campus Talca, Talca 3460000, Chile.
Escuela de Medicina, Universidad de Talca, Campus Talca, Talca 3460000, Chile.
Int J Mol Sci. 2022 Dec 19;23(24):16222. doi: 10.3390/ijms232416222.
Amyotrophic lateral sclerosis (ALS) is a disease that progressively annihilates spinal cord motor neurons, causing severe motor decline and death. The disease is divided into familial and sporadic ALS. Mutations in the TAR DNA binding protein 43 (TDP-43) have been involved in the pathological emergence and progression of ALS, although the molecular mechanisms eliciting the disease are unknown. Transposable elements (TEs) and DNA sequences capable of transposing within the genome become dysregulated and transcribed in the presence of TDP-43 mutations. We performed RNA-Seq in human motor neurons (iMNs) derived from induced pluripotent stem cells (iPSCs) from TDP-43 wild-type-iMNs-TDP-43-and mutant-iMNs-TDP-43-genotypes at 7 and 14 DIV, and, with state-of-the-art bioinformatic tools, analyzed whether TDP-43 alters both gene expression and TE activity. Our results show that TDP-43 induced global changes in the gene expression and TEs levels at all in vitro stages studied. Interestingly, many genetic pathways overlapped with that of the TEs activity, suggesting that TEs control the expression of several genes. TEs correlated with genes that played key roles in the extracellular matrix and RNA processing: all the regulatory pathways affected in ALS. Thus, the loss of TE regulation is present in TDP-43 mutations and is a critical determinant of the disease in human motor neurons. Overall, our results support the evidence that indicates TEs are critical regulatory sequences contributing to ALS neurodegeneration.
肌萎缩侧索硬化症（ALS）是一种逐渐破坏脊髓运动神经元的疾病，导致严重的运动功能衰退和死亡。该疾病分为家族性和散发性 ALS。TAR DNA 结合蛋白 43（TDP-43）的突变与 ALS 的病理发生和进展有关，尽管诱发疾病的分子机制尚不清楚。转座元件（TEs）和能够在基因组内转位的 DNA 序列在 TDP-43 突变存在时会失调并转录。我们在 7 和 14 DIV 时，用来自诱导多能干细胞（iPSCs）的人类运动神经元（iMNs）进行了 RNA-Seq，这些 iMNs 来自 TDP-43 野生型-iMNs-TDP-43-和突变型-iMNs-TDP-43-基因型，并利用最先进的生物信息学工具，分析了 TDP-43 是否改变了基因表达和 TE 活性。我们的结果表明，TDP-43 在所有体外研究阶段都诱导了基因表达和 TE 水平的全局变化。有趣的是，许多遗传途径与 TE 活性重叠，表明 TE 控制着许多基因的表达。TEs 与在细胞外基质和 RNA 处理中起关键作用的基因相关：所有受 ALS 影响的调控途径。因此，TE 调节的丧失存在于 TDP-43 突变中，是人类运动神经元疾病的关键决定因素。总的来说，我们的结果支持了这样的证据，即 TE 是导致 ALS 神经退行性变的关键调节序列。
