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

PloS One
Brian J HensonRobert D Nicholls

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 m...Continue Reading

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Jun 4, 2013·Annual Review of Neuroscience·Andrew K GrovesDonna M Fekete
Jul 31, 2013·PloS One·Ece SelçukArzu Karabay
Oct 13, 2016·PloS One·Mariano SerraoFrancesco Pierelli
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Nov 17, 2020·Frontiers in Cellular Neuroscience·Tao JiangMinghui Tan

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Methods Mentioned

BETA
immunoprecipitation
ChIP
PCR
transfection
transfections
Protein Assay
electrophoresis

Software Mentioned

Ensembl
TargetScan
ClustalW
SPAST
BLAST
NIH ImageJ

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