Mechanisms Underlying the Survival of Adult Generated Neurons

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The brain possesses an innate ability to generate new neurons from dividing neural precursor cells throughout adulthood. Surprisingly, of the thousands of cells that are generated, the vast majority of them die as they mature, thus proliferation of precursor cells only results in a few newly generated neurons. In order to manipulate or promote neurons to survive and signal within the brain, it is imperative to better understand the molecular pathways that regulate NPC survival. ***The studies proposed in this grant, arises from our discovery that a protein called cyclin dependent kinase 5 (Cdk5) is essential for the survival of neural precursor cells. This led our lab into the search for other proteins within the cells that make up the Cdk5-mediated survival pathway. Our data suggests that Cdk5 is required for survival of precursor cells due to its interaction with a protein called Bcl-2, which counteracts cell death, in a cell death process called apoptosis. Bcl-2 interacts with a protein called Beclin1, which is important for regulating an intracellular cleaning process called autophagy, which can also regulate cell death through its interaction with apoptosis. Thus together we have converging lines of evidence to support that the survival of neural precursor cells in the adult brain requires Cdk5-dependent regulation of the apoptotic and autophagic pathways. To test this hypothesis we will use transgenic mice models and viral gene transfer into the mouse brain, so that we can remove, or manipulate the expression of Cdk5, Bcl-2 or beclin1 from the neural precursor cells and determine how these pathways interact in regulating survival of these cells within the complex environment of the brain. ***These results provide novel insight into how neural precursor cells survive to develop into a new neurons in the brain, as well as further our understanding of the complex relationship between apoptosis and autophagy that controls whether cells survive or die. Our findings aim to provide the world with the knowledge required to enable development of treatments that could potentially modify the new neurons in the treatment of many diseases, which would provide enormous benefit to Canadians. In addition this work will benefit Canada by helping recruit and retain highly trained scientists, as well as train the next generation of neuroscientists to tackle the many unknowns related to the brain and mind.********