Research Projects

Over the past decade, several studies have conclusively shown the causal relationship between dysregulated lysophosphatidylserine (lyso-PS) metabolism and/or signaling to an array of human neurodegenerative and autoimmune diseases. More recently, deleterious mutations to the major lyso-PS synthase, ABHD16A, have been linked to a complex form of Hereditary Spastic Paraplegia (HSP), a progressive human neurodegenerative disease. Given our long-standing interest in studying lyso-PS metabolism and signaling, and the emergence of yet another disease associated with dysregulated lyso-PS metabolism and/or signaling, we propose the following three goals: 1. Biochemical characterization of human ABHD16A towards establishing a detailed sequence-activity relationship for this lipase 2. Lipidomic and behavioral characterization of the ABHD16A knockout mice, towards understanding how ABHD16A deletion causes complex HSP 3. Development of an ABHD16A-null fly line, as an alternative animal model to study complex HSP Hypothesis and key questions: 1. ABHD16A deletion leads to reduced lyso-PS concentrations in the brain. Yet, biochemically, ABHD16A remains poorly characterized, and how mutations to ABHD16A affect its lipase activity remain unknown. Can a detailed sequence-activity relationship serve as a predictive tool for understanding why mutations to human ABHD16A might result in loss of its enzymatic activity leading to complex HSP? 2. Several neurodegenerative diseases have been modeled in mice, including those involving dysregulated lyso-PS metabolism/signaling. Hence, can ABHD16A knockout mice serve as an animal model to understand how the mutations to this lipase causes complex HSP? Can an age-dependent profile of brain lyso-PS metabolism, behavior and neuroanatomy help establish how complex HSP progresses in humans due to the lack of ABHD16A activity? 3. Fly models serve as an accelerated animal model for studying age-dependent (or late onset) human neurogenerative diseases. Can we identify a fly-homolog of human ABHD16A, and develop an ABHD16A-null fly model to serve as another animal model to study complex HSP?