Defective RNA metabolism in motor neurons from Amyotrophic Lateral Scelosis patients

神经退行性疾病的特征是特定类型的神经元死亡。运动神经元疾病肌萎缩侧索硬化症(ALS)和脊髓性肌萎缩症(SMA)分别由剪接体成分SnRNPs生物发生所必需的TDP-43、RNA结合蛋白和SMN功能障碍引起。然而，这些疾病常见的RNA代谢缺陷仍不清楚。我们发现TDP-43通过与SMN复合体结合定位于核宝石中，并参与剪接体的维持。此外，在TDP-43病理的FTLD中，GEM丢失，U-SnRNA水平上调，剪接体U-SnRNPs异常并广泛聚集在ALS运动神经元的核中，而在FTLD的颞叶中未见聚集。综上所述，这些发现表明剪接体稳定性的崩溃是ALS和SMA中常见的神经退变的关键过程，并可能解释运动神经元的细胞类型特异性脆弱性。

Neurodegenerative diseases are characterized by the death of specific type of neurons. The motor neuron diseases amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA) are caused by dysfunction of TDP-43, RNA-binding protein and SMN, essential for biogenesis of spliceosomal component snRNPs, respectively. However, the defects in RNA metabolism common to these diseases remain unclear. We show that TDP-43 localizes in nuclear gems through association with the SMN complex, and is involved in spliceosome maintenance. Moreover, gems are lost, U snRNA levels are up-regulated and spliceosomal U snRNPs abnormally and extensively accumulate in the nuclei of ALS motor neurons but not in the temporal lobe of FTLD with TDP-43 pathology. Together, these findings indicate that collapse of spliceosome stability is the critical process common to neurodegeneration in ALS and SMA, and may explain cell-type specific vulnerability of motor neurons.