Neuronal Mechanisms of Metabolic and Genetic Defects of the Peroxisome

PROJECT SUMMARY Peroxisomes are fundamental sub-cellular organelles present in all eukaryotic cells. Peroxisomes participate in a number of biochemical pathways including catabolism of very-long-chain fatty acids, branched chain fatty acids, and bile acids, the biosynthesis of plasmalogen lipids, and

mediate a number of crucial biological processes. Human diseases due to lack of peroxisomes are severe multisystem diseases These conditions, called peroxisome biogenesis disorders, Zellweger-spectrum disorders (PBD-ZSD) illustrate how peroxisomes are required for human health. Insights from studies in PBD-ZSD have been applied to common disease such as

Alzheimer’s disease. In order to probe the molecular mechanisms that underlie PBD-ZSD I use genomics, untargeted metabolomics and genetic technology in Drosophila. I am a dedicated physician-scientist devoting my career to the study of PBD-ZSD, having made several contributions. First, I have used metabolomics to define a pattern of biochemical abnormalities or

a “PBD-ZSD Metabolome” a characteristic signature of these diseases that interestingly includes reduced sphingomyelins, a previously unrecognized biomarker of PBD-ZSD. Second, my lab has used innovative genetic technology in Drosophila to further probe consequences of peroxisomal biology for neurons. For example, in a large forward genetic screen on the Drosophila X-

chromosome we identified novel genes that alter peroxisomes in vivo and we have shown these are candidate neurological disease genes. Finally, using genomics I have developed a track record of diagnosing undiagnosed individuals who have novel or unique mutations in genes such as ACOX1, DNM1L, PEX1 and PEX16, and these studies point to novel genetic mechanisms for

peroxisomal disease. Based on my studies of sphingomyelin I hypothesize that peroxisomal dysfunction leads to altered composition of the side-chains of sphingomyelins resulting in impaired neurological function in PBD-ZSD. I also propose, based on animal model studies that peroxisomes are required both during development and during aging for nervous system function.

Finally, my preliminary data suggests that de novo mutations can impact peroxisomal genes, which are traditionally considered “autosomal recessive” and can be an important mechanism for peroxisomal disease. In this proposal we use clinical studies, unique model organism technology and genomic and metabolomic technology to test these hypotheses and advance studies of PBD-

ZSD towards better diagnosis, treatment and improved quality of life for patients.