UBC Theses and Dissertations

UBC Theses Logo

UBC Theses and Dissertations

Behavioural investigation of normal and mutant human presenilin functions in caenorhabditis elegans Bozorgmehr, Tahereh

Abstract

Presenilins are well known as sites of mutations responsible for early-onset Alzheimer's disease. The normal functions of presenilins and the mechanisms by which presenilins cause Alzheimer disease are not yet known. Conservation of cellular and molecular functions between the C.elegans and human genes makes it a powerful experimental model organism to investigate cellular mechanisms of Alzheimer's disease and neurodegenerative disorders in general. Mutations in the C.elegans presenilin1homologue, sel-12, decrease Notch signaling activity, which results in an egg-laying deficit in these animals. It has been well established that pathogenic PS1 mutations impair Notch signaling; however, in the first part of this thesis we showed that a recently discovered PS1Δs₁₆₉ human mutation rescued the egg-laying deficit associated with Lin12/Notch pathway, suggesting that in this pathogenic PS1 mutation Notch processing remained intact. In the second part of this thesis the behavioural phenotypes of a mutation in the C.elegans presenilin homologue, sel-12, were studied. Our results revealed that a mutation in the sel-12 gene causes chemotaxis deficits toward volatile and water-soluble stimuli in sel-12 mutant animals. Reintroducing the sel-12 or the wild-type human presenilin gene decreased those behavioural phenotypes, indicating that the observed chemotaxis deficits were dependent on sel-12 activity. However, rescuing with the human PS1C₄₁₀Y mutation, which has a severe effect on Notch processing, did not ameliorate the chemotaxis deficit; in contrast, rescuing with PS1Δs₁₆₉ rescued both volatile and water-soluble chemotaxis impairments suggesting that the chemotaxis deficit causing by sel-12 mutation depends on the Notch pathway.

Item Citations and Data

License

Attribution-NonCommercial-NoDerivs 2.5 Canada

Usage Statistics