JBC：ALS密集蛋白聚集体成分确定
研究者们为战胜肌萎缩性脊髓侧索硬化症(ALS)提供了一条重要的新线索，他们发现引起ALS神经衰退的密集蛋白质聚集体只含有一种蛋白质——超氧化物歧化酶（SOD1）。相关论文发表在3月份的《生物化学杂志》（Journal of Biological Chemistry）上。
正常情况下，SOD1是一种保护细胞不受自由基损伤的蛋白质，当突变的SOD1发生聚集时，就是一种遗传性ALS标志信号，以前这些聚集体的确切成份并不清楚。鉴定聚集体中所含的蛋白质以及它们是否受到修饰，有助于弄清它们的组成结构以及它们为什么能造成这么大的伤害。
Julian Whitelegge及其同事Joan S. Valentine和David Borchelt利用质谱揭示了这些聚集体的成份，而且发现了一些令人惊讶的结果，他们发现这些聚集体几乎完全由SOD1组成（有些样品含有痕量的随机神经蛋白，似乎是偶然出现的）。
此外，他们分析ALS小鼠脊索发现，几乎所有的SOD1都是完整的蛋白质，而不是不完整或被破坏的片断。而且，研究者们未发现存在化学修饰的证据（仅指不易被DTT处理掉的修饰）。
然而，关于这些聚集体仍有很多问题待解决，文章中的研究结果只是给了科学家们一个起点，指出聚集体是突变SOD1的一种固有特性，很类似阿兹海默症中的淀粉斑。（来源：EurekAlert!中文版）
生物谷推荐原始出处：
（Journal of Biological Chemistry），Vol. 283, Issue 13, 8340-8350，Joan S. Valentine，Julian P. Whitelegge
Detergent-insoluble Aggregates Associated with Amyotrophic Lateral Sclerosis in Transgenic Mice Contain Primarily Full-length, Unmodified Superoxide Dismutase-1*
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From the Departments of Chemistry and Biochemistry and the **NPI-Semel Institute, David Geffen School of Medicine, UCLA, Los Angeles, California 90095, the Department of Chemistry, Occidental College, Los Angeles, California 90041, the ¶Department of Neuroscience, Santa Fe Health Alzheimer's Disease Research Center, McKnight Brain Institute, University of Florida, Gainesville, Florida 32611, and the ||Department of Neurology, University of Massachusetts Medical School, Worcester, Massachusetts 01605
Determining the composition of aggregated superoxide dismutase 1 (SOD1) species associated with amyotrophic lateral sclerosis (ALS), especially with respect to co-aggregated proteins and post-translational modifications, could identify cellular or biochemical factors involved in the formation of these aggregates and explain their apparent neurotoxicity. The results of mass spectrometric and shotgun-proteomic analyses of SOD1-containing aggregates isolated from spinal cords of symptomatic transgenic ALS mice using two different isolation strategies are presented, including 1) resistance to detergent extraction and 2) size exclusion-coupled anti-SOD1 immunoaffinity chromatography. Forty-eight spinal cords from three different ALS-SOD1 mutant mice were analyzed, namely G93A, G37R, and the unnatural double mutant H46R/H48Q. The analysis consistently revealed that the most abundant proteins recovered from aggregate species were full-length unmodified SOD1 polypeptides. Although aggregates from some spinal cord samples contained trace levels of highly abundant proteins, such as vimentin and neurofilament-3, no proteins were consistently found to co-purify with mutant SOD1 in stoichiometric quantities. The results demonstrate that the principal protein in the high molecular mass aggregates whose appearance correlates with symptoms of the disease is the unmodified, full-length SOD1 polypeptide.
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