Identifying Pathogenic Protein Aggregates in ALS through Autocatalytic Misfolding

通过自催化错误折叠识别 ALS 中的致病蛋白聚集体

基本信息

  • 批准号:
    7432574
  • 负责人:
  • 金额:
    $ 15.11万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2007
  • 资助国家:
    美国
  • 起止时间:
    2007-07-01 至 2012-06-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Amyotrophic lateral sclerosis (ALS) is an incurable disease marked by a relentless dying-off of motor neurons that causes paralysis then death. Ninety percent of cases occur sporadically and the cause of these cases is not known. Strong evidence indicates that abnormal aggregation of some cell protein or proteins causes sporadic ALS, but these proteins have not been conclusively identified, nor has the cause of the aggregation been determined. The hypothesis behind our proposal is that protein aggregation in ALS is driven by a self-propagating, or "autocatalytic" process of protein aggregation that is analogous to the process of aggregation that causes prion diseases, but involves a protein different from the prion protein. We aim to exploit recently developed methods, known as protein misfolding cyclic amplification (PMCA), that efficiently propagate aggregated prion protein in vitro to identify this putative protein that aggregates to cause ALS. In outline, the procedure we propose is as follows: A small amount ("seed") of homogenized spinal cord tissue from persons who died of sporadic ALS will be mixed with a larger amount of normal spinal cord tissue. Simultaneously, a homogenate of normal cord seeded with normal cord will be prepared. The two homogenate mixes will be subjected to a modified PMCA procedure. Putative autocatalytically aggregating proteins from the ALS spinal cord will cause the same protein to specifically aggregate in the normal cord. We will compare the aggregated proteins in the two samples. Those proteins that aggregate only when "seeded" by ALS cord are likely to be autocatalytic aggregates and potentially the cause of sporadic ALS. PMCA procedures were not designed for the proteome-wide studies we proposed, so we will systematically modify the procedures to minimize non-autocatalytic aggregation while maintaining autocatalytic aggregation, using the prion protein as a surrogate for the putative ALS-causing protein. We will also use PMCA to look for autocatalytic aggregation of TDP-43, a protein recently identified to aggregate in spinal cord neurons of persons with sporadic ALS. These studies have the potential to determine the cause of sporadic ALS, a disease that kills almost 6000 Americans annually, and for which there is no effective treatment. A specific target protein and a pathogenic process for curative therapies may be identified. Further, if successful, the approach can be readily modified to use as an tool for high-throughput screening of potentially therapeutic compounds.
肌萎缩侧索硬化症(ALS)是一种无法治愈的疾病,其特征是运动神经元的无情死亡,导致瘫痪然后死亡。90%的病例是零星发生的,这些病例的原因尚不清楚。强有力的证据表明,一些细胞蛋白质或蛋白质的异常聚集导致散发性ALS,但这些蛋白质尚未最终确定,也没有确定聚集的原因。我们提出的假设是,ALS中的蛋白质聚集是由蛋白质聚集的自传播或“自催化”过程驱动的,该过程类似于导致朊病毒疾病的聚集过程,但涉及不同于朊病毒蛋白的蛋白质。我们的目标是利用最近开发的方法,被称为蛋白质错误折叠循环扩增(PMCA),有效地传播聚集的朊病毒蛋白在体外,以确定这种推定的蛋白质,聚集导致ALS。概括地说,我们提出的程序如下:将少量(“种子”)来自死于散发性ALS的人的均质化脊髓组织与大量正常脊髓组织混合。同时,制备接种正常脐带的正常脐带匀浆。将对两种匀浆混合物进行改良的PMCA程序。来自ALS脊髓的推定的自催化聚集蛋白质将导致相同的蛋白质在正常脊髓中特异性聚集。我们将比较两个样本中的聚集蛋白。这些蛋白质聚集时,只有“播种”的ALS索可能是自催化的聚集体和潜在的原因散发性ALS。PMCA程序不是为我们提出的蛋白质组范围的研究而设计的,因此我们将系统地修改程序,以最大限度地减少非自催化聚集,同时保持自催化聚集,使用朊病毒蛋白作为推定的ALS引起蛋白质的替代品。我们还将使用PMCA来寻找TDP-43的自催化聚集,TDP-43是一种最近发现在散发性ALS患者的脊髓神经元中聚集的蛋白质。这些研究有可能确定散发性ALS的病因,这种疾病每年导致近6000名美国人死亡,并且没有有效的治疗方法。可以鉴定用于治愈性疗法的特定靶蛋白和致病过程。此外,如果成功的话,该方法可以很容易地被修改,以用作高通量筛选潜在治疗化合物的工具。

项目成果

期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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PATRICK J BOSQUE其他文献

PATRICK J BOSQUE的其他文献

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{{ truncateString('PATRICK J BOSQUE', 18)}}的其他基金

Identifying Pathogenic Protein Aggregates in ALS through Autocatalytic Misfolding
通过自催化错误折叠识别 ALS 中的致病蛋白聚集体
  • 批准号:
    7315459
  • 财政年份:
    2007
  • 资助金额:
    $ 15.11万
  • 项目类别:
ECTOPIC EXPRESSION OF THE PRION PROTEIN
朊病毒蛋白的异位表达
  • 批准号:
    2460460
  • 财政年份:
    1995
  • 资助金额:
    $ 15.11万
  • 项目类别:
ECTOPIC EXPRESSION OF THE PRION PROTEIN
朊病毒蛋白的异位表达
  • 批准号:
    2750775
  • 财政年份:
    1995
  • 资助金额:
    $ 15.11万
  • 项目类别:
ECTOPIC EXPRESSION OF THE PRION PROTEIN
朊病毒蛋白的异位表达
  • 批准号:
    2260062
  • 财政年份:
    1995
  • 资助金额:
    $ 15.11万
  • 项目类别:
ECTOPIC EXPRESSION OF THE PRION PROTEIN
朊病毒蛋白的异位表达
  • 批准号:
    2260063
  • 财政年份:
    1995
  • 资助金额:
    $ 15.11万
  • 项目类别:
ECTOPIC EXPRESSION OF THE PRION PROTEIN
朊病毒蛋白的异位表达
  • 批准号:
    2891386
  • 财政年份:
    1995
  • 资助金额:
    $ 15.11万
  • 项目类别:

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