Maintaining the brain: insight into human neurodegeneration from Drosophila melanogaster mutants

Abstract

More than 40 Drosophila melanogaster genes have been discovered for which recessive, loss-of-function mutations cause adult onset degeneration of the central nervous system (CNS). A table presenting these genes is provided, and an expanded, updated version can be found at the Bonini laboratory homepage. Almost all of these genes have easily identifiable orthologues in the mouse and human. Over half have mouse or human orthologues that are also associated with neurodegeneration. The swiss cheese (sws) gene demonstrates the value of unbiased screens in the fly. Since its discovery, two biochemical functions have been characterized for the protein; loss of the mouse orthologue in the brain has been shown to cause neurodegeneration, and loss-of-function mutations in the human orthologue have been discovered as the cause of spastic paraplegia 39. Pink1 and park are associated with Parkinson's disease, and they demonstrate the value of epistasis experiments in the fly, which have shown that these two genes function together in a pathway that regulates mitochondrial fusion and fission. Fly neurodegeneration genes can be grouped into the following cellular processes: mitochondrial function, signal transduction, lipid homeostasis, protein homeostasis and the cytoskeleton. Many of the genes have roles in more than one of these processes. Some glial-specific genes have been shown to be required for maintaining neurons in the adult. Mutations in other, more widely expressed genes have defective glia, underscoring the importance of glia in CNS integrity. Many genetic tricks are possible in the fly, such as: the precise control in space and time of the expression of transgenes, including through RNAi constructs; and the possibility of making marked homozygous mutant clones as small as a single neuron in otherwise heterozygous animals. These techniques, and the ease of forward genetics screens for identifying new neurodegeneration mutants, ensure that D. melanogaster will remain a key tool for the analysis of genes required for CNS integrity.