Metabolomics Reveals a Novel Therapeutic for Multiple Sclerosis

Mon 11:00 AM - Track 2: Therapeutic Metabolomics

Leah P. Shriver The Scripps Research Institute

Leah P. Shriver, Department of Cell Biology, The Scripps Research Institute Gary Patti, Department Molecular Biology and the Center for Mass Spectrometry, The Scripps Research Institute Bridgit Crews, Millennium Laboratories Oscar Yanes, Department Molecular Biology and the Center for Mass Spectrometry, The Scripps Research Institute Gary Siuzdak, Department Molecular Biology and the Center for Mass Spectrometry, The Scripps Research Institute Marianne Manchester, The Department of Cell Biology, The Scripps Research Institute

Multiple Sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system that affects over 2 million individuals worldwide. Current therapies are not effective for all patients and do not prevent the accumulation of neurological disability over time. Metabolomics measures the end products of both gene and protein expression to determine the physiological state of the tissue or cell during normal function and disease states. We used liquid chromatography mass spectrometry to perform an untargeted metabolomics screen to identify metabolites altered in lesions from MS patients and in two animal models of MS; experimental autoimmune encephalomyelitis (EAE) and mouse hepatitis virus infection (MHV). Significant upregulation of a number of acylcarnitine species was seen in the spinal cords of EAE and MHV mice as well as in MS patients with active inflammatory lesions. Treatment of mice with an inhibitor of carnitine palmitoyltransferase-1 (CPT-1), the enzyme that regulates the import of acylcarnitines into the mitochondria, reduced disease severity. Mice treated with this drug showed decreased levels of inflammatory cells in the CNS that coincided with a reduction in acylcarnitine species. These results suggest that upregulation of fatty acid oxidation plays a role in inflammatory lesion formation during autoimmune demyelination. Therapeutic metabolomics has uncovered a novel metabolic pathway associated with central nervous system inflammation that may lead to new therapies for MS.

Email: lshriver@scripps.edu

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