LIST OF SESSIONS I Diseases and Aging II Patterning and cell fate determination III Differentiation of neurons and glia IV Channels

This article may be used for research, teaching and private study purposes. Any substantial or systematic reproduction, redistribution , reselling , loan or sub-licensing, systematic supply or distribution in any form to anyone is expressly forbidden. The publisher does not give any warranty express or implied or make any representation that the contents will be complete or accurate or up to date. The accuracy of any instructions, formulae and drug doses should be independently verified with primary sources. The publisher shall not be liable for any loss, actions, claims, proceedings, demand or costs or damages whatsoever or howsoever caused arising directly or indirectly in connection with or arising out of the use of this material. Recent years have seen a revolution in research into ageing, with the discovery of mutations in single genes that extend healthy lifespan. Drosophila has played and continues to play a key role in these discoveries. Evidence is accumulating that extension of lifespan is accompanied by a broad-spectrum improvement in health at later ages, and amelioration of specific ageing-related pathologies, including neurodegeneration. The neurodegenerative mutant blue cheese links lipid metabolism with lysosomal function Many studies suggest a link between sphingolipid metabolism and neurodegeneration. The objective of our work is to understand the relationship between sphingolipid activity and neurodegeneration, using Drosophila genetics. We have evidence suggesting that the regulation of sphingolipid metabolism and trafficking in cells may be similar in Drosophila and mammals. We report on the characterization of blue cheese (bchs), a lysosomal protein with a highly conserved BEACH domain. This motif is required for sphingomyelinase (SMase) activation by the protein FAN in response to stress signals. Overexpression or loss of function of Bchs results in neurodegeneration accompanied by axonal transport defects and alterations in brain sterol levels and storage. Bchs' possible role in sphingomyelin cleavage raises the possibility that cholesterol storage is regulated by modulations in the levels of a SM-like lipid in the fly. Consistent with the biochemical data, genetic evidence links bchs-induced neurodegenera-tion to altered sphingolipid and cholesterol metabolism, with ceramide levels being the critical factor. Overexpres-sion or loss of function in ceramidase or SMase modulate the degenerative phenotype. As a complement to the genetic and biochemical data, we are carrying out mass spectrometric analyses of sphingolipid alterations in bchs. In summary, the degenerative phenotype in bchs reveals mechanisms that interconnect sphingolipid and cholesterol regulation with neurodegeneration. and Organophosphate Toxicity acts as a …