Roles of Cdk5 in neurodevelopment and neurodegeneration

在过去的一年里，我们在对衰老和神经退行性变的理解方面取得了两项重大进展。在前一年，我们已经证明，无菌炎症-在没有感染的情况下发生的炎症反应-是我们神经退行性疾病模型中神经元细胞死亡的主要原因。然而，在这个过程中，我们意识到，当我们在没有正常细菌微生物组的情况下培养动物时，衰老过程的整个结构似乎发生了变化。今年，我们详细研究了这一点，发现我们通常认为是正常衰老的一部分的过程中，有70%实际上与衰老没有必然的联系。相反，它们是动物体内发生的变化，因为它对生活在动物身上和动物体内的细菌的变化特性做出反应。这从根本上改变了我们对衰老的看法，因为我们长期以来认为是衰老过程核心的许多过程原来是免疫学的方面，而不是衰老。我们的实验还确定了30%的与年龄相关的过程，这些过程不依赖于动物的细菌种群;这些过程更可能是衰老过程所固有的。我们取得的另一个重大进展是令人惊讶的发现，在亨廷顿病中突变的HTT基因和在阿尔茨海默病中编码β-淀粉样蛋白的基因APP实际上是一个分子机器的两个部分。两者都编码Abl酪氨酸激酶的调节因子，Abl酪氨酸激酶是慢性髓细胞性白血病和急性淋巴细胞性白血病的主要部分中的致病基因，其也是神经布线的发展和维持的中心。值得注意的是，HTT和APP有一种跷跷板的关系，HTT抑制Abl，APP激活它，它们的作用是使Abl保持在一个中间水平的活动，这是产生和维持神经结构所必需的。我们现在知道HTT和APP突变体的发育缺陷实际上是由于Abl活性的改变; HD和AD的变性是否也部分由于Abl的改变是进一步研究的关键问题。

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.