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Giovanni Lesa

Dr Giovanni Lesa

Dr Giovanni Lesa

Research Fellow

Grants awarded

The cellular role of complex lipids in the nematode C. elegans

Scheme: University Research Fellowship

Organisation: University College London

Dates: Oct 2008-Sep 2012

Value: £328,698.40

Summary: We focus on understanding the cellular role of glycosphingolipids (GSLs), fats particularly enriched in brain cells. Altered levels of GSLs cause serious, often fatal, human diseases. It is unclear, however, how altered amounts of these fats lead to cell dysfunction. Understanding the cellular role of fats has been very difficult because they are not easily studied using traditional biochemical techniques. For this reason, we have developed a new, genetic approach, which employs a simple organism called C. elegans. We have engineered mutant strains unable to produce GSLs. They arrest growth very early during development and display severe defects in specific cells of the digestive tract. However, when we made those cells (and only those cells) produce again GSLs, we rescued the defects associated with GSL depletion, indicating that GSLs are only required there. We discovered that GSL-depleted animals display defects in autophagy, a process normally used by cells to remove and break down organelles and long-lived proteins. These are first collected in an organelle called autophagosome and then degraded in the lysosome. Defects in autophagy have been implicated in several pathologies, including neurodegenerative diseases and cancer. In GSL-depleted animals, the cells that require GSLs specifically accumulate abnormally high levels of autophagosomes that, we hypothesize, are toxic for those cells. Indeed, when we artificially decreased autophagosome formation, we could ameliorate the growth arrest associated with loss of GSLs. Importantly, autophagosome degradation is also defective in mammalian cells depleted of GSLs. Our data, therefore, suggest that GSLs are required to degrade autophagosomes efficiently not only in C. elegans but also in mammals. Our goal is to understand the molecular basis of GSL function on autophagy by combining the powerful genetics of C. elegans with the many tools available to study autophagy and trafficking in human cells.

Scheme: University Research Fellowship

Organisation: University College London

Dates: Oct 2003-Sep 2008

Value: £287,871.95

Summary: This project summary is not available for publication.

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