Cabaj Maximilian, Mazzara Pietro G, Gaertner Zachary A, Wang Ruizhi, Pauers Michaela M, Randolph Lisa K, Roque Cláudio Gouveia, Feeney Sean, Raimo Serena, de Prisco Nicola, Chemiakine Alexei, Wang Xinyuan, Singh Ravi K, Rajasekaran Swetha, Yalamanchili Hari K, Miles Wayne, Baldwin Kristin, Zhang Chaolin, Harms Matthew B, Khurana Vikram, Brandt Vicky, Hengst Ulrich, Awatramani Rajeshwar, Gennarino Vincenzo A
Department of Genetics and Development, Columbia University Irving Medical Center, New York, NY, USA.
Department of Neurology, Northwestern University, Chicago, IL, USA.
Cell Rep. 2025 Aug 26;44(8):116145. doi: 10.1016/j.celrep.2025.116145. Epub 2025 Aug 13.
The protein α-synuclein, encoded by SNCA, accumulates in Parkinson's disease (PD) and other synucleinopathies for reasons that remain unclear. Here, we investigated whether SNCA is regulated in vivo by the RNA-binding protein PUM1. We establish that PUM1 binds to SNCA's 3' UTR in mouse and human cells. In induced neurons from patients with SNCA locus triplication, PUM1 mRNA levels are lower than in healthy controls, but increasing PUM1 normalizes both SNCA mRNA and α-synuclein protein levels, largely by suppressing the long 3' UTR SNCA isoform. In microfluidic chamber experiments, silencing PUM1 causes a redistribution of SNCA between the soma and axons. We also show that the previously described miR-7 regulation of SNCA mRNA requires PUM1. Lastly, we report finding several individuals with PD in clinical databases bearing variants in PUM1 that affect its RNA-binding ability. Understanding how RNA-binding proteins regulate α-synuclein could lead to viable new therapies for synucleinopathies.
由SNCA编码的蛋白质α-突触核蛋白在帕金森病（PD）和其他突触核蛋白病中积累，其原因尚不清楚。在此，我们研究了RNA结合蛋白PUM1在体内是否对SNCA有调控作用。我们证实PUM1在小鼠和人类细胞中与SNCA的3'UTR结合。在SNCA基因座三倍体患者的诱导神经元中，PUM1 mRNA水平低于健康对照，但增加PUM1可使SNCA mRNA和α-突触核蛋白水平正常化，这主要是通过抑制长3'UTR的SNCA异构体实现的。在微流控腔室实验中，沉默PUM1会导致SNCA在胞体和轴突之间重新分布。我们还表明，先前描述的miR-7对SNCA mRNA的调控需要PUM1。最后，我们报告在临床数据库中发现了几个患有PD的个体，其PUM1存在影响其RNA结合能力的变体。了解RNA结合蛋白如何调控α-突触核蛋白可能会为突触核蛋白病带来可行的新疗法。
