Role of Apolipoprotein D and Its Homologs, in Normal and Pathological Aging, in Drosophila melanogaster

Citation

Muffat, Julien A. (2009) Role of Apolipoprotein D and Its Homologs, in Normal and Pathological Aging, in Drosophila melanogaster. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/H1ST-ZY74. https://resolver.caltech.edu/CaltechETD:etd-05182009-232337

Abstract

The free radical theory of aging is probably the most enduring one to date. It stipulates that, in the process of normal cellular function, in particular due to oxygen-based respiration, reactive oxygen species are formed. These constantly put a strain on the cell, damaging lipids in the membranes, causing protein aggregation and loss-of-function, or mutations in the genome. Over time, this accumulated damage overcomes the repair potential of a given cell, and scaled up to an entire organism, results in the deterioration seen in normal aging. Under these assumptions, age-related pathologies are only an acceleration of the process in a given tissue, leading to the emergence of the pathology over the noise of normal aging. In the past decade, invertebrates such as Drosophila melanogaster and C. elegans have provided invaluable insight into these processes and the canonical pathways that regulate them. This success is owed in part to the power of the genetic tools available, to their relatively short lifespans, and to the wide arrays of phenotypes that can be studied. We set out to study a particular protein, Glaz, whose overexpression enables fruitflies to live 30% longer than normal. This protein was identified as a hit from a screen looking at an accelerated aging paradigm, placing fruitflies in 100% oxygen. While an interesting protein in its own right, it was through its homology with mammalian Apolipoprotein D (ApoD), that our interest was truly piqued. ApoD and its homologs turn out to be fascinating proteins, upregulated by various stresses and in age-related diseases such as cancers and Alzheimer’s. We showed, in our model organism of choice, that this upregulation is part of a beneficial stress response. Understanding and harnessing its functions can only help provide therapeutic approaches for a wide range of disorders.

Thesis Files