Spastin (SPG4) regulatory mechanisms studied

New targets found for mutation and therapeutic drug screening.


Factors affecting the genetic transcription (copying over) and regulation of the amount of Spastin protein produced have been defined in this study. They represent new targets for examining what goes wrong in cases of SPG4 HSP and what needs to be compensated for or corrected.


Hereditary spastic paraplegias (HSPs) comprise a group of neurodegenerative disorders that are characterized by progressive spasticity of the lower extremities, due to axonal degeneration in the corticospinal motor tracts.


HSPs are genetically heterogeneous and show autosomal dominant inheritance in ~70–80% of cases, with additional cases being recessive or X-linked. The most common type of HSP is SPG4 with mutations in the SPAST gene, encoding spastin, which occurs in 40% of dominantly inherited cases and in ~10% of sporadic cases.


Both loss-of-function and dominant-negative mutation mechanisms have been described for SPG4, suggesting that precise or stoichiometric levels of spastin are necessary for biological function. Therefore, we hypothesized that regulatory mechanisms controlling expression of SPAST are important determinants of spastin biology, and if altered, could contribute to the development and progression of the disease. To examine the transcriptional and post-transcriptional regulation of SPAST, we used molecular phylogenetic methods to identify conserved sequences for putative transcription factor binding sites and miRNA targeting motifs in the SPAST promoter and 3′-UTR, respectively.


By a variety of molecular methods, we demonstrate that SPAST transcription is positively regulated by NRF1 and SOX11. Furthermore, we show that miR-96 and miR-182 negatively regulate SPAST by effects on mRNA stability and protein level. These transcriptional and miRNA regulatory mechanisms provide new functional targets for mutation screening and therapeutic targeting in HSP.


SOURCE: PLoS ONE 7(5): e36505.   doi:10.1371/journal.pone.0036505 © 2012 Henson et al.


Transcriptional and Post-Transcriptional Regulation of SPAST, the Gene Most Frequently Mutated in Hereditary Spastic Paraplegia


Brian J. Henson1, Wan Zhu2, Kelsey Hardaway1, Jaime L. Wetzel1, Mihaela Stefan1, Kathryn M. Albers3, Robert D. Nicholls1,2*


1 Birth Defects Laboratories, Division of Medical Genetics, Department of Pediatrics, Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania, United States of America, 2 Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania, United States of America, 3 Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America



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