Spinal muscular atrophy (SMA) is a neuromuscular disorder caused by homozygous mutation or deletion of the survival motor neuron 1 (SMN1) gene. A second copy, SMN2, is similar to SMN1 but produces ∼10% SMN protein because of a single-point mutation that causes splicing defects. Chronic low levels of SMN cause accumulation of co-transcriptional R-loops and DNA damage leading to genomic instability and neurodegeneration in SMA. Severity of SMA disease correlates inversely with SMN levels. SMN2 is a promising target to produce higher levels of SMN by enhancing its expression. Mechanisms that regulate expression of SMN genes are largely unknown. We report that zinc finger protein ZPR1 binds to RNA polymerase II, interacts in vivo with SMN locus and upregulates SMN2 expression in SMA mice and patient cells. Modulation of ZPR1 levels directly correlates and influences SMN2 expression levels in SMA patient cells. ZPR1 overexpression in vivo results in a systemic increase of SMN levels and rescues severe to moderate disease in SMA mice. ZPR1-dependent rescue improves growth and motor function and increases the lifespan of male and female SMA mice. ZPR1 reduces neurodegeneration in SMA mice and prevents degeneration of cultured primary spinal cord neurons derived from SMA mice. Further, we show that the low levels of ZPR1 associated with SMA pathogenesis cause accumulation of co-transcriptional RNA-DNA hybrids (R-loops) and DNA damage leading to genomic instability in SMA mice and patient cells. Complementation with ZPR1 elevates senataxin levels, reduces R-loop accumulation and rescues DNA damage in SMA mice, motor neurons and patient cells. In conclusion, ZPR1 is critical for preventing accumulation of co-transcriptional R-loops and DNA damage to avert genomic instability and neurodegeneration in SMA. ZPR1 enhances SMN2 expression and leads to SMN-dependent rescue of SMA. ZPR1 represents a protective modifier and a therapeutic target for developing a new method for the treatment of SMA.

中文翻译：

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ZPR1防止R环积累，上调SMN2表达并挽救脊髓性肌萎缩。

脊髓性肌萎缩症（SMA）是由纯合突变或存活运动神经元1（SMN1）基因缺失引起的一种神经肌肉疾病。第二个副本SMN2与SMN1类似，但由于导致拼接缺陷的单点突变而产生了约10％的SMN蛋白。慢性低水平的SMN会导致共转录R环的积累和DNA损伤，从而导致SMA中的基因组不稳定和神经变性。SMA疾病的严重程度与SMN水平成反比。SMN2是通过增强其表达来产生更高水平的SMN的有希望的靶标。调节SMN基因表达的机制在很大程度上是未知的。我们报告锌指蛋白ZPR1绑定到RNA聚合酶II，在体内与SMN基因座相互作用，并在SMA小鼠和患者细胞中上调SMN2表达。ZPR1水平的调节直接关联并影响SMA患者细胞中SMN2的表达水平。体内ZPR1的过表达导致SMN水平全身升高，并挽救SMA小鼠中的重度至中度疾病。ZPR1依赖的抢救改善了生长和运动功能，并延长了雄性和雌性SMA小鼠的寿命。ZPR1减少了SMA小鼠的神经变性，并防止了源自SMA小鼠的培养的原代脊髓神经元的变性。此外，我们显示与SMA发病机理相关的低水平ZPR1会导致共转录RNA-DNA杂种（R环）的积累和DNA损伤，从而导致SMA小鼠和患者细胞中的基因组不稳定。与ZPR1互补可提高senataxin水平，减少R环积累并挽救SMA小鼠，运动神经元和患者细胞中的DNA损伤。总之，ZPR1对于防止共转录R环的积累和防止SMA中基因组不稳定性和神经变性的DNA损伤至关重要。ZPR1增强SMN2的表达并导致SMN依赖的SMA抢救。ZPR1代表保护性修饰剂和治疗靶标，可用于开发治疗SMA的新方法。