Dec 17, 2015
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| Carolyn Hoff Lynch Room Inquiries please contact Camille Pride at campride@sas.upenn.edu Title: A lipid signaling pathway that controls immune cell extravasation in a human neurological disease Abstract: Understanding hereditary human disorders has benefited from DNA sequencing technologies, which have, to date, facilitated determination of the genetic basis for over 4,000 inherited diseases in humans. Assigning biochemical and cellular functions to the proteins encoded by these mutated genes is critical to achieve a deeper mechanistic understanding of human genetic disorders and for identifying potential treatment strategies for these diseases. Several hereditary nervous system diseases are caused by deleterious mutations in poorly characterized enzymes from the serine hydrolase class. PHARC (polyneuropathy, hearing loss, ataxia, retinal pigmentation, cataract) is one such neurological disease, caused by deleterious null mutations in the Abhd12 gene, which encodes the serine hydrolase ABHD12. The major symptoms of PHARC include polymodal sensorimotor defects linked to peripheral neuropathy, hearing loss, early onset of cataract and blindness, cerebellar atrophy and demyelination of sensorimotor neurons. The Cravatt lab determined using Abhd12–/– mice and lipidomics that ABHD12 serves as a major lysophosphatidylserine (lyso-PS) lipase in the mammalian brain, degrading lyso-PS to produce glycerophosphoserine (GPS) and free fatty acid (FFA). Recently we have identified and functionally annotated ABHD16A as the principal phosphatidylserine (PS) lipase in the mammalian central nervous system and the immune system, where it regulates immunomodulatory lyso-PS production. Our studies thus designate ABHD16A as a key enzyme that functions upstream of ABHD12, and that these enzymes together form a dynamic pathway for regulating lyso-PS signaling in vivo. Furthermore we have found that lyso-PS lipids are intricately involved in immune cell trafficking, and are in particular critical for the extravasation of T-cells into tissues. I will present our lipidomics and immunological findings in mouse genetic models that support the broader role for the ABHD16A-ABHD12-lyso-PS signaling network in (neuro)-immunology.
