Morsani College of Medicine
Department of Molecular Medicine
Joint and Affiliate Faculty
Post-Doctorates / Research Associates
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Master's of Science Program
Allergy, Immunology and Infectious Diseases
USF Health Byrd Alzheimer's Institute
Children's Research Institute (CRI)
Center for Drug Discovery and Innovation
H. Lee Moffitt Cancer Center
James A Haley Veteran's Hospital
Bay Pines VA Healthcare System
Assoc Professor, COLLEGE OF MEDICINE MOLECULAR MEDICINE
My research focuses on the mechanisms of neurodegeneration in Alzheimer’s disease (AD) and related neurological disorders. AD is the leading cause of dementia and most prevalent neurodegenerative disease, affecting more than 40 million people worldwide. Pathologically, brains afflicted with AD are riddled with accumulations of two highly toxic proteins, namely amyloid beta and tau, which are the underlying cause of neurodegeneration. The amyloid beta protein is derived from 2 proteolytic cuts made in its precursor protein, APP, and it is widely believed that Abeta induces early neurogeneration and promotes pathology associated with the tau protein.
In my lab, we utilize various molecular, biochemical, cell biological, and animal modeling tools to answer important questions pertinent to healthy and pathological neuronal function. Some of these tools include confocal microscopy, fluorescence live cell imaging, calcium imaging, axonal transport of cargo proteins & organelles, generation & use of transgenic and knockout models, in vivo neurogenesis / neuronal migration assays, cell death assays, and membrane protein trafficking assays, etc. Broad questions directly relevant to our ongoing studies are the following. 1) What are the molecular pathways and therapeutic targets of Abeta generation? 2) What are the molecular pathways and therapeutic targets of Abeta-induced neurotoxicity? 3) How do Abeta-neurotoxic pathways induce synaptic damage, mitochondrial dysfunction, and tau pathology? 4) What are some naturally protective mechanisms and pathways against neurodegeneration?
My earlier work originally identified the genetic association of LRP, an apoE receptor, to late-onset AD. Later work by us and others found that LRP plays a dual and opposing role in APP metabolism: 1) sequestration and removal of secreted amyloid beta protein and 2) promotion of Abeta generation by increasing APP processing. We recently found that LRP is required for the majority of Abeta generation by promoting the trafficking APP to lipid rafts, cholesterol-rich intracellular microdomains highly enriched in Abeta generating proteases. We narrowed the Abeta promoting region of LRP to the C-terminal 37 residues. Using a yeast 2-hybrid screen, we identified several new proteins, which interact with the C-terminal 37 residues of LRP cytoplasmic tail (C37). One such C37 interacting protein was Ran-Binding Protein 9 (RanBP9), a multimodular scaffolding protein. We found that LRP and APP interact with each other on the neuronal surface, and RanBP9 helps to stabilize this interaction, which accelerates their internalization from the cell surface. Such endocytic event is critical for the generation of Abeta, and RanBP9 levels are highly increased in brains of AD patients and animal models of AD. We have also found that RanBP9 interacts with and helps to internalize integrins from the cell surface, thereby disrupting cell adhesions while simultaneously increasing Abeta production. On the other hand, integrins are critical for transmitting the toxic Abeta signals from the cell surface through a series of events (i.e. disruption of focal adhesions) that require RanBP9 and a downstream apoptotic / actin-binding protein, cofilin, eventually leading to the disruption of cell/synaptic integrity and mitochondrial function. Our working hypothesis based on experimental findings is that cell surface receptors and their intracellular pathways that promote the generation of Abeta are largely identical to the very pathways that transmit the neurotoxic signals induced by Abeta (i.e. integrins / LRP / APP / RanBP9 / Cofilin, etc.). In collaboration with Drs. Uversky and Chen in our department, we are also using biophysical and computational tools to structurally define various molecular targets for rational drug design in addition to the screening of compound libraries for AD therapeutics.
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The Ferreira laboratory focuses on the heme biosynthetic pathway, which consists of eight enzyme-catalyzed reactions. Heme biosynthesis occurs under the control of the enzyme 5-Aminolevulinate synthase (ALAS), which catalyzes the first and rate-limiting reaction of succinyl-CoA with glycine to produce 5-aminolevulinate (ALA), CoA, and CO2. Loss-of-function and gain-of-function mutations in human erythroid ALAS (ALAS2) have been associated with two diseases, x-linked sideroblastic anemia (XLSA) and x-linked dominant protoporphyria (XLDPP), respectively. In XLDPP, the gain-of-function of the ALAS2 enzyme causes extreme photosensitivity resulting from protoporphyrin IX accumulation in the skin of patients. Although the mutations associated with XLSA occur throughout the ALAS2 gene, those associated with XLDPP all correspond to modifications in the C-terminus of the mature enzyme. The 26 C-terminal amino acids of mature ALAS2 are highly conserved, and yet differ from those in ALAS1, the housekeeping ALAS isoform, suggesting that the C-terminus may play an important role in erythroid-specific regulation. The overall hypothesis of my project is that the C-terminal region of ALAS2 provides specific regulatory mechanisms of heme biosynthesis to precursor erythroid cells.