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Sci Rep. 2017 Aug 15;7(1):8295. doi: 10.1038/s41598-017-07603-z.

Deregulation of ZPR1 causes respiratory failure in spinal muscular atrophy.

Author information

1
Center of Emphasis in Neurosciences, Texas Tech University Health Sciences Center, El Paso, TX, 79905, USA.
2
Department of Biomedical Sciences, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, TX, 79905, USA.
3
Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center, El Paso, TX, 79905, USA.
4
Center of Emphasis in Neurosciences, Texas Tech University Health Sciences Center, El Paso, TX, 79905, USA. Laxman.Gangwani@ttuhsc.edu.
5
Department of Biomedical Sciences, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, TX, 79905, USA. Laxman.Gangwani@ttuhsc.edu.
6
Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center, El Paso, TX, 79905, USA. Laxman.Gangwani@ttuhsc.edu.

Abstract

Spinal muscular atrophy (SMA) is caused by the low levels of survival motor neuron (SMN) protein and is characterized by motor neuron degeneration and muscle atrophy. Respiratory failure causes death in SMA but the underlying molecular mechanism is unknown. The zinc finger protein ZPR1 interacts with SMN. ZPR1 is down regulated in SMA patients. We report that ZPR1 functions downstream of SMN to regulate HoxA5 levels in phrenic motor neurons that control respiration. Spatiotemporal inactivation of Zpr1 gene in motor neurons down-regulates HoxA5 and causes defects in the function of phrenic motor neurons that results in respiratory failure and perinatal lethality in mice. Modulation in ZPR1 levels directly correlates and influences levels of HoxA5 transcription. In SMA mice, SMN-deficiency causes down-regulation of ZPR1 and HoxA5 that result in degeneration of phrenic motor neurons. Identification of ZPR1 and HoxA5 as potential targets provides a paradigm for developing strategies to treat respiratory distress in SMA.

PMID:
28811488
PMCID:
PMC5557895
DOI:
10.1038/s41598-017-07603-z
[Indexed for MEDLINE]
Free PMC Article

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