Roles of Cdk5 in neurodevelopment and neurodegeneration

National Institute Of Neurological Disorders And Stroke

Investigators

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Abstract

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.