Transcriptional and post-transcriptional regulation of spast, the gene most frequently mutated in hereditary spastic paraplegia

Brian J. Henson, Wan Zhu, Kelsey Hardaway, Jaime L. Wetzel, Mihaela Stefan, Kathryn M. Albers, Robert D. Nicholls

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Article numbere36505
JournalPLoS One
Volume7
Issue number5
DOIs
StatePublished - May 4 2012
Externally publishedYes

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Hereditary Spastic Paraplegia
MicroRNAs
Genes
mutation
microRNA
Gene encoding
3' Untranslated Regions
Transcription
Mutation
Screening
Transcription Factors
genes
conserved sequences
Binding Sites
neurodegenerative diseases
3' untranslated regions
disease course
Messenger RNA
Pyramidal Tracts
Conserved Sequence

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Transcriptional and post-transcriptional regulation of spast, the gene most frequently mutated in hereditary spastic paraplegia. / Henson, Brian J.; Zhu, Wan; Hardaway, Kelsey; Wetzel, Jaime L.; Stefan, Mihaela; Albers, Kathryn M.; Nicholls, Robert D.

In: PLoS One, Vol. 7, No. 5, e36505, 04.05.2012.

Research output: Contribution to journalArticle

Henson, Brian J. ; Zhu, Wan ; Hardaway, Kelsey ; Wetzel, Jaime L. ; Stefan, Mihaela ; Albers, Kathryn M. ; Nicholls, Robert D. / Transcriptional and post-transcriptional regulation of spast, the gene most frequently mutated in hereditary spastic paraplegia. In: PLoS One. 2012 ; Vol. 7, No. 5.
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