Transcriptional and post-transcriptional regulation of SPAST, the gene most frequently mutated in hereditary spastic paraplegia.
Transcriptional and post-transcriptional regulation of SPAST, the gene most frequently mutated in hereditary spastic paraplegia.
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DOI：
10.1371/journal.pone.0036505
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Nicholls RD
中科院分区：
文献类型：
--
作者：
Henson BJ;Zhu W;Hardaway K;Wetzel JL;Stefan M;Albers KM;Nicholls RD
遗传性痉挛性截瘫（HSP）包括一组神经退行性疾病，其特征在于由于皮质脊髓运动束中的轴突变性导致下肢进行性痉挛。热休克蛋白是遗传异质性的，在70-80%的病例中显示出常染色体显性遗传，另外的病例是隐性的或X连锁的。最常见的HSP类型是SPG 4，其SPAST基因突变编码痉挛素，其发生在40%的显性遗传病例和约10%的散发病例中。SPG 4的功能丧失和显性失活突变机制均已被描述，这表明精确或化学计量水平的痉挛素对生物学功能是必要的。因此，我们假设控制SPAST表达的调节机制是痉挛蛋白生物学的重要决定因素，如果改变，可能有助于疾病的发展和进展。为了研究SPAST的转录和转录后调控，我们使用分子系统发育方法分别鉴定SPAST启动子和3′-UTR中假定的转录因子结合位点和miRNA靶向基序的保守序列。通过多种分子方法，我们证明SPAST转录受NRF 1和SOX 11的正调控。此外，我们发现miR-96和miR-182通过影响mRNA稳定性和蛋白水平来负调控SPAST。这些转录和miRNA调控机制为HSP突变筛选和治疗靶向提供了新的功能靶点。
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.
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影响因子：
64.8
作者：
Baek, Daehyun;Villen, Judit;Shin, Chanseok;Camargo, Fernando D.;Gygi, Steven P.;Bartel, David P.
通讯作者：
Bartel, David P.
DOI：
10.1126/science.1162327
发表时间：
2009-06-26
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Badis G;Berger MF;Philippakis AA;Talukder S;Gehrke AR;Jaeger SA;Chan ET;Metzler G;Vedenko A;Chen X;Kuznetsov H;Wang CF;Coburn D;Newburger DE;Morris Q;Hughes TR;Bulyk ML
通讯作者：
Bulyk ML
DOI：
10.1016/j.bbrc.2003.12.065
发表时间：
2004-01-30
影响因子：
3.1
作者：
Choi, YS;Kim, S;Pak, YK
通讯作者：
Pak, YK
影响因子：
11
作者：
de Bot, S. T.;van den Elzen, R. T. M.;Scheffer, H.
通讯作者：
Scheffer, H.
DOI：
10.1083/jcb.200309096
发表时间：
2004-01-19
期刊：
The Journal of cell biology
影响因子：
--
作者：
Ciani L;Krylova O;Smalley MJ;Dale TC;Salinas PC
通讯作者：
Salinas PC