ZPRI prevents R-loop accumulation, upregulates SMN2 expression and rescues spinal muscular atrophy

Spinal muscular atrophy (SMA) is a neuromuscular disorder caused by homozygous mutation or deletion of the survival motor neuron (SMA1) gene. A second copy, SMN2, is simiiar to SMA1 but produces similar to 10% SMN protein hecaasr 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 a promising target to produce higher levels of SMN by enhancing its expression. Mechanisms that regulate expression of SAN genes are largely unknown. We report that zinc finger protein 71 R1 binds to RNA polyinerase II, interacts in vivo with SMA locus and upregulates SMN2 expression in SMA mice and patient cells. Modulation of ZPR1 levels directly correlates and intlue.SMN2 expression levels in SMA patient cells. ZPR1 over expression in vivo results in a systemic finer se of SMN levels and rescues severe to moderate disease in SMA mice. ZPRI-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 ZPRI associated with SMA pathogenesis cause accumulation of co-transcriptional RNADNA hybrids (R-loops; and DNA damage leading to genornic 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 Rloops and DNA damage to avert genomic instability and neurodegeneration in SN1A. ZPRI enhances SMN2 expression and leads to SMN-dependent rescue of SMA. ZPRI represents a protective modifier and a therapeutic target for developing a new method for the treatment of SMA.