Neurodegeneration Pathway-Specific Mutagenesis

Most Alzheimer’s disease does not “run in families.” Only rare families are afflicted with Alzheimer’s disease that is caused by inherited defects in any one of three genes. In these unfortunate families, approximately half the children inherit the defective gene and are destined to develop Alzheimer’s disease in late middle age. Although the most common form of Alzheimer’s occur in old age and does not have a simple pattern of inheritance, the genetic make-up of the individual does influence the chance of becoming ill. Rather than a single gene, many genes are involved. Identification of the genes that influence Alzheimer’s disease will help in developing treatments that could low the progress of disease or even prevent it from occurring. Identification of the defective genes causing the familial form of Alzheimer’s disease was a major accomplishment, even though only a single gene is involved in each family. When many genes are involved, study of human populations is extremely difficult. The laboratory mouse is much more suitable for studies of this kind. Unfortunately, due to their short lifespan, very few mutations relevant to diseases old age have been identified in mice. We propose to induce mutation that are relevant to Alzheimer’ disease and to a related disease by using a DNA-damaging chemical. We will specifically select for mutations that affect only mice that lack the amyloid precursor protein (APP) gene or the prion protein (PrP) gene. A fragment of APP protein is deposited in the brains of Alzheimer’s disease patient and is associated with the death of brain cells. An improperly folded form of PrP causes prion diseases , which also cause brain cell death. Although much is known about how these protein act in disease, their normal function is unknown. Genes involved in their normal function are likely to also affect disease processes involving the proteins. We are exploiting the power of mouse genetics to identify genes involved in human brain disorders.