Neurodegenerative disorders, both sporadic and inherited, are associated commonly with aging. The wide variety of likely mechanisms of action in different neurodegenerative disorders suggests that common features of normal aging underlie the increased predisposition to suffer from neurodegenerative disorders. The age dependence of neurodegeneration is unexplained and is a fundamental problem in understanding these common pathologies. Understanding the interaction of aging with neurodegeneration requires the development of model systems in which the rates of aging and neurodegeneration can be varied systematically. The development of murine genetic models of polyglutamine (polyQ) diseases with varying phenotypes and the existence of mouse lines with retarded aging offers the opportunity to develop models in which the interaction of aging and neurodegeneration can be studied systematically. We propose to develop compound mice lines carrying alleles that cause polyQ disease phenotypes and alleles that retard normal aging to study the impact of altering aging on the polyQ disease-like phenotypes. We focus on a phylogenetically conserved signaling pathway that influences aging in several invertebrate and vertebrate species;the Growth Hormone-insulin/IGF - Aki - FOXO pathway. Our hypothesis is that retarding aging by disrupting the Growth Hormone - insulin/IGF - Akt - FOXO pathway will delay mortality, and retard the development of behavioral and pathologic abnormalities secondary to induced polyQ mutations. This hypothesis is supported by impressive work in invertebrates but has not been tested in mammals.
Our specific aims are: 1) To generate compound mutant mice carrying a dominant HD-like transgene responsible for a moderately aggressive phenotype and 2 copies of a null mutation at the Pit1 (Snell dwarf) locus. 2) To generate compound mutant mice carrying a dominant HD-like transgene responsible for a moderately aggressive phenotype and 2 copies of a null mutation mutation at the Growth Hormone receptor (GHR) locus. 3) To characterize the lifespan, and behavioral and pathologic features of these compound mutants. Our long term goal is to understand the interaction of aging and neurodegeneration. If these experiments are successful, we will have models in hand to study the aging-neurodegeneration relationship. These models would be useful in dissecting the specific mechanisms underlying the aging-neurodegeneration relationship. We would be able to vary the rate of neurodegeneration by developing additional compound models with more slowly progressive polyQ disease alleles. We would be able to extend these approaches also to other neurodegenerations such as Alzheimer disease and Motor Neuron disease.
The onset of most degenerative brain diseases, like Alzheimer disease and Parkinson disease, occurs later in life. Some unknown features of aging make the human brain susceptible to these degenerative disorders. We propose to develop new mouse models that will allow analysis of the interaction of normal aging and neurodegeneration.
