Roles of Cdk5 in neurodevelopment and neurodegeneration

Cdk5 在神经发育和神经变性中的作用

• 批准号: 10460393
• 负责人: edward giniger
• 金额: $ 168.81万
• 依托单位: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10460393
• 关键词: Acute Lymphocytic Leukemia; Adult; Aging; Alzheimer' s Disease; Amyloid Beta A4 Precursor Protein; Amyloid beta-Protein; Animals; Architecture; Axon; Bacteria; Cell physiology; Chronic Myeloid Leukemia; Defect; Dendrites; Development; Drosophila genus; Event; Genes; Genomic approach; Huntington Disease; Immunology; Infection; Inflammation; Inflammatory Response; Maintenance; Modeling; Molecular Machines; Mutate; Nerve Degeneration; Neurodegenerative Disorders; Phosphotransferases; Play; Population; Process; Property; Proteins; Proto-Oncogene Proteins c-abl; Role; Sterility; Structure; System; Testing; age related; bacteriome; experimental study; mutant; neurodevelopment; neuron development; neuron loss; normal aging; programs; relating to nervous system

In the past year we have made two major advances in our understanding of aging and neurodegeneration. In the preceding year, we had shown that sterile inflammation - an inflammatory response that occurs in the absence of infection - was a major cause of neuronal cell death in our model of neurodegenerative disease. In the process, however, we realized that the whole architecture of the aging process seemed to be altered when we grew animals in the absence of their normal bacterial microbiome. In the current year we have examined this in detail, and discovered that 70% of the processes that we normally think of as being part of normal aging, actually have no necessary connection to aging at all. Rather, they are changes that occur in the animal as it responds to the changing properties of the bacteria that live on and in the animal. This fundamentally changes our view of aging, since many of the processes that we have long thought are central to the process turn out to be aspects of immunology, not aging. Our experiments also identify the 30% of age-related processes that are NOT dependent on the bacterial population of the animal; these are more likely to be intrinsic to the aging program. The other major advance we made was the surprising discovery that the HTT gene, which is mutated in Huntingtons Disease, and APP, the gene that encodes beta-amyloid in Alzheimers Disease, are actually two parts of a single molecular machine. Both encode regulators of the Abl tyrosine kinase, the causative gene in Chronic Myelogenous Leukemia and in a substantial fraction of acute Lymphocytic Leukemia that is also central to the development and maintenance of neural wiring. Remarkably, HTT and APP have a see-saw relationship where HTT suppresses Abl and APP activates it. Between them their role is to keep Abl at an intermediate level of activity that is essential to producing and maintaining neural structure. We now know that developmental defects in HTT and APP mutants are actually due to altered activity of Abl; whether degeneration in HD and AD are also due in part to altered Abl is a crucial question for further study.

在过去的一年中，我们在对衰老和神经变性的理解方面取得了两个重大进步。在过去的一年中，我们表明，在我们的神经退行性疾病模型中，无菌炎症 - 在没有感染的情况下发生的炎症反应 - 是神经元细胞死亡的主要原因。然而，在此过程中，我们意识到，当我们在没有正常细菌的微生物组的情况下生长动物时，衰老过程的整个结构似乎正在改变。在当年，我们对此进行了详细检查，并发现我们通常认为是正常衰老的一部分的70％的过程实际上与衰老没有必要的联系。相反，它们是动物中发生的变化，因为它响应了生活在动物和动物中的细菌的变化。这从根本上改变了我们对衰老的看法，因为我们长期以来一直认为该过程的许多过程被证明是免疫学的方面，而不是衰老的方面。我们的实验还确定了不依赖动物细菌种群的年龄相关过程的30％。这些更有可能是衰老计划的固有。我们做出的另一个主要进步是令人惊讶的发现，在亨廷顿疾病中突变的HTT基因和APP是在阿尔茨海默氏病中编码β-淀粉样蛋白的基因，实际上是单分子机器的两个部分。两者都编码ABL酪氨酸激酶的调节剂，慢性骨髓性白血病中的致病基因以及大量急性淋巴细胞性白血病，这也是神经接线发展和维持的核心。值得注意的是，HTT和应用具有远见关系，HTT抑制ABL并激活应用程序。他们之间的作用是将ABL保持在产生和维持神经结构至关重要的活动水平。我们现在知道，HTT和APP突变体中的发育缺陷实际上是由于ABL活性的改变。 HD和AD的变性是否也部分归因于ABL的改变是进一步研究的关键问题。