THE RELATIONSHIP BETWEEN AUTOPHAGY, CELL SURVIVAL AND CELL DEATH IN A MODEL OF NEURODEGENERATION AND DEVELOPMENT.

Abstract

The catabolic degradation of proteins is vital for the proper function and homeostasis of all cells. Autophagy is one of the major catabolic systems, and it is involved in processes that are as diverse as cell survival, cell death, immune reaction, cancer and neurodegeneration. Neurodegenerative diseases often have the pathology of protein accumulation in inclusions, but it is unclear whether these inclusions cause cell toxicity. Here I show that autophagy has protective functions in a model of a polyglutamine neurodegenerative disease in Drosophila. Inhibition of autophagy in this model enhances polyglutmine-induced degeneration, while activation of autophagy suppresses degeneration. Moreover, I observed similar protein aggregates in the larval salivary glands of a Drosophila dynein light chain mutant. This dynein light chain mutant is defective in autophagy, and their salivary glands fail to execute developmentally regulated programmed cell death. Ectopic activation of autophagy is sufficient to suppress the protein accumulation in dynein light chain mutant salivary glands. Both neurons and salivary glands are long-lived post-mitotic cells, and these cells are likely to have unique catabolic needs. Our data indicate that defects in catabolism are responsible for the neurodegenerative and salivary gland cell death defects that I observed, and could explain the association of autophagy with neurodegenerative diseases.