Graduation Year
2006
Document Type
Dissertation
Degree
Ph.D.
Degree Granting Department
Biochemistry and Molecular Biology
Major Professor
Huntington Potter, Ph.D.
Committee Member
R. Ken Keller, Ph.D.
Committee Member
David Morgan, Ph.D.
Committee Member
Larry P. Solomonson, Ph.D.
Committee Member
Maxine Sutcliffe, Ph.D.
Keywords
aneuploidy, cell cycle, mitosis, in situ hybridization, Down Syndrome
Abstract
Mutations in the presenilin 1 gene account for most early-onset familial Alzheimer's disease (FAD). The presenilins and AD may also be related through a common involvement in the cell cycle. Here we report that one important aspect of the cell cycle---proper chromosome segregation---is dependent on presenilin function and therefore may be involved in AD pathogenesis. Specifically we find that FAD mutations in presenilin 1 (M146L and M146V) lead to chromosome missegregation and aneuploidy in vivo and in vitro: 1) Both metaphase chromosome analysis and in situ hybridization reveal significant aneuploidy in the lymphocytes and neurons of PS-1 transgenic mice. 2) Transiently transfected human cells expressing normal and, especially, mutant PS-1 develop aneuploidy within 48 hours, including trisomy 21, while cells transfected with dominant negative PS-1 genes lacking ?-secretase activity have no effect on chromosome segregation. 3) Analysis of mitotic spindles in the transfected cells reveals abnormal microtubule arrays and lagging chromosomes. The possible mechanisms by which cell cycle defects and chromosome missegregation induced by y-secretase may contribute to Alzheimer's disease will be discussed.
Scholar Commons Citation
Boeras, Debrah I., "Chromosome Missegregation in Alzheimer’s Disease Caused by Presenilin 1" (2005). USF Tampa Graduate Theses and Dissertations.
https://digitalcommons.usf.edu/etd/2786
