Baylor医学院的研究人员在8月26日的Cell杂志上公布了他们有关神经疾病的新的研究成果。
Huda Zoghbi博士和同事确定出了一种确实能提高ataxin-1蛋白（失调症蛋白质1）正常活性的遗传突变。虽然疾病spinocerebellar ataxia type1（脊髓小脑运动失调症）比较罕见，但是这一发现对了解类似的、更加常见的疾病有重要意义。
之前，Huda Zoghbi博士发现，在spinocerebellar ataxia type1中，ataxin-1基因中重复碱基（CAG）的数量异常多（CAG的大量重复导致谷氨酸的产生）。
研究人员将携带80个重复的异常的ataxin-1蛋白引入小鼠，从而造成了Purkinje细胞（一种神经元）发生了退化并导致小鼠发生共济失调。当将携带30个重复的大量正常蛋白引入小鼠还能导致异常的神经元功能。这意味着正常的和突变形式的ataxin-1都具有坏的功能，但突变形式更加有效，而正常的蛋白的水平过高时也会变成毒素。
作者简介：
Huda Y. Zoghbi
E-mail: hzoghbi@bcm.tmc.edu
Professor, Baylor College of Medicine
Investigator, Howard Hughes Medical Institute
B.S., American University of Beirut, Lebanon, 1976
M.D., Meharry Medical School, Nashville, TN, 1979
Postdoc, Baylor College of Medicine, Houston, TX, 1985-88
Neural development, neurodegenerative and neurodevelopmental disorders
My laboratory uses genetic and cell biological approaches to explore the pathogenesis of polyglutamine neurodegenerative diseases and Rett syndrome, and to study genes essential for normal neurodevelopment.
Several dominantly inherited spinocerebellar ataxias (SCAs) are caused by expansion of a CAG repeat that encodes glutamine in the respective proteins. We discovered that ataxin-1 with an expanded glutamine tract accumulates in neurons of patients and mouse models and redistributes components of the protein folding and degradation machinery. We hypothesized that mutant ataxin-1 misfolds and resists degradation, and confirmed this model with studies showing that ataxin-1 toxicity is suppressed by chaperone overexpression but exacerbated by disruptions in the ubiquitin proteasome pathway (Cummings 1999, 2001).
To uncover other pathogenic pathways besides protein degradation, we collaborated with Dr. Juan Botas to generate an SCA1 fly model and perform genetic screens (Fernández-Fúnez 2000). We are now examining the most potent modifiers in SCA1 mice and trying to understand ataxin-1's normal function.
We discovered that mutations in the X-linked encoding methyl CpG-binding protein 2 (MECP2) cause Rett syndrome, a leading cause of mental retardation in girls (Amir 1999). Affected children appear to develop normally for the first six to 18 months of life, then lose acquired cognitive and motor skills. MECP2 mutations are now known to cause other phenotypes, such as autism, mild learning disability, and even psychosis or severe retardation with spasticity in males. We found that MeCP2, which is thought to be involved in gene silencing via DNA methylation, plays some special role in mature neurons. To begin to address the pathogenesis of Rett we generated mice carrying a truncating mutation similar to one that causes classic Rett in human females; these mice reproduce most of the features of Rett syndrome, including the unusual forelimb stereotypes (Shahbazian 2002). We are now conducting pathogenesis studies and interventional trials in MECP2 mice.
My lab identified Math1, the mouse homolog of Drosophila atonal, a gene essential for coordination and balance. Math1 null mice die shortly after birth due to respiratory failure and lack cerebellar granule neurons, inner ear hair cells, and multiple components of the proprioceptive pathway (Bermingham 2001). In the gut, Math1 is essential for development of secretory (paneth, goblet, and enteroendocrine) cells. In collaboration with Dr. Hugo Bellen we found that Math1 and atonal functionally substitute for each other in flies and mice, respectively. A conditional allele is allowing us to analyze Math1's postnatal function in different components of the proprioceptive pathway and in CNS control of breathing.
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Selected Publications
Amir RE, Van den Veyver IB, Wan M, Tran CQ, Francke U, Zoghbi HY (1999) Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nature Genetics 23:185-188.
Fernández-Fúnez P, Niño-Rosales ML, de Gouyon B, She W-C, Luchack JM, Martinez P, Turiegano E, Benito J, Capovilla M, Skinner PJ, McCall A, Canal I, Orr HT, Zoghbi HY, Botas J (2000) Identification of genes that modify ataxin-1-induced neurodegeneration. Nature 408:101-106.
Cummings CJ, Sun Y, Opal P, Antalffy B, Mestril R, Orr HT, Dillmann WH, Zoghbi HY (2001) Over-expression of inducible HSP70 chaperone suppresses neuropathology and improves motor function in SCA1 mice. Human Molecular Genetics 10:1511-1518.
Bermingham NA, Hassan BA, Wang VY, Fernandez M, Banfi S, Bellen HJ, Fritzsch B, Zoghbi HY (2001) Proprioceptor pathway development is dependent on Math1. Neuron 30:411-422.
Yang Q, Bermingham NA, Finegold MJ, Zoghbi HY (2001) Requirement of Math1 for secretory cell lineage commitment in the mouse intestine. Science 294:2155-2158.
Watase K, Weeber EJ, Xu B, Antalffy B, Yuva-Paylor L, Hashimoto K, Kano M, Atkinson R, Sun Y, Armstrong DL, Sweatt JD, Orr HT, Paylor R, Zoghbi HY (2002) A long CAG repeat in the mouse Sca1 locus replicates SCA1 features and reveals the impact of protein solubility on selective neurodegeneration. Neuron 34:905-919.
Shahbazian MD, Young JI, Yuva-Paylor LA, Spencer CM, Antalffy BA, Noebels JL, Armstrong DL, Paylor R, Zoghbi HY (2002) Mice with truncated MeCP2 recapitulate many Rett syndrome features and display hyperacetylation of histone H3. Neuron 35:243-254.
Yoo SY, Pennesi ME, Weeber EJ, Xu B, Atkinson R, Chen S, Armstrong DL, Wu SM, Sweatt JD, Zoghbi HY (2003) SCA7 knockin mice model human SCA7 and reveal gradual accumulation of mutant ataxin-7 in neurons and abnormalities in short-term plasticity. Neuron 37:383-401.
Chen HK, Fernández-Fúnez P, Acevedo SF, Lam YC, Kaytor MD, Fernandez MH, Aitken A, Skoulakis EM, Orr HT, Botas J, Zoghbi HY (2003) Interaction of Akt-phosphorylated ataxin-1 with 14-3-3 mediates neurodegeneration in spinocerebellar ataxia type 1. Cell 113:457-468.
