Browsing by Subject "Amyloid"
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Item Characterization of the Roles of Intrinsically Disordered Regions from RNA-Binding Proteins in Phase Separation(2016-05-27) Lin, Yuan; Ross, Elliott M.; Liu, Qinghua; Tu, Benjamin; Rosen, Michael K.Eukaryotic cells organize complex biochemical reactions through compartmentalization. While many intracellular compartments are enclosed by membranes, others are not. Messenger ribonucleoprotein (mRNP) granules are membrane-less organelles that enrich RNA and RNA-binding proteins containing intrinsically disordered regions (IDRs). I demonstrate that IDRs, coupled with RNA binding domain and RNA, can phase separate in vitro, producing dynamic liquid droplets. Over time, these droplets mature into more stable states, as assessed by slowed fluorescence recovery after photobleaching and resistance to salt. Maturation often coincides with the formation of fibrous structures. Pathological mutation within IDRs leads to the acceleration of maturation. Different disordered domains can co-assemble into phase-separated droplets. In the case of the IDR from FUS (fused in sarcoma), I show that tyrosine residues are important in promoting phase separation. Either mutation of these aromatic residues or phosphorylation of the IDR disassembles liquid droplets. I further discover that the disassembly is due to the disruption of aromatic interactions mediated by critical tyrosine residues and therefore an increase in the overall solubility of proteins. Taken together, these studies demonstrate a plausible mechanism by which interactions between IDRs, coupled with RNA binding, could contribute to mRNP granule assembly in vivo by promoting phase separation. Progression from dynamic liquids to stable fibers may be regulated to produce cellular structures with diverse physiochemical properties and functions. Misregulation of maturation could contribute to diseases that are associated with aberrant mRNP granules. Posttranslational modifications of IDRs could modulate the assembly and disassembly of mRNP granules by altering the solubility of IDRs.Item Increased Amyloid Deposition after TBI Correlates with Cognitive Deficits and Symptom Worsening(2016-01-19) Sherman, Matt; Gatson, Joshua; Stebbins, Cari; Kilianski, Joseph; Madden, Christopher; Wolf, Steven E.; Diaz-Arrastia, Ramon; Batjer, Hunt; Minei, JosephBACKGROUND: Traumatic brain injury (TBI) is a risk factor for Alzheimer's disease (AD). The primary objective of this case-series study was to conduct early 18F-AV-45 (florbetapir F18) positron emission tomography (PET) imaging in mild-to-moderate TBI subjects after injury to determine if amyloid plaque load predicts cognitive deficits. METHODS: Serial florbetapir F18 PET imaging was conducted in 7 individuals with a mild or moderate TBI (as indicated by their Glasgow Coma Scale [GCS] score between 13 and 15) at day 14 and at 12 months after injury. Of the 7 subjects that were tested, only one had a moderate TBI. Amyloid plaque levels were measured in the cerebral cortex of each individual. To screen for cognitive deficits, the symbol match test was administered at 12 months after TBI. RESULTS: At day 14 after injury, compared to healthy controls, the mild and moderate TBI subjects (N=7) had a 10% increase in amyloid plaque load within the cerebral cortex. When stratified by cognitive outcomes, at day 14 after injury, the subjects with poor outcomes (n=3) experienced a 20% and 13% increase in brain amyloid compared to healthy controls and TBI subjects with good outcomes, respectively. With respect to cognition, at 12 months after injury, the subjects with poor outcomes exhibited a negative correlation (r= -0.71) between amyloid plaque load and cognitive performance. Also, a positive correlation (r=+0.78) was detected between increased brain amyloid load and symptom scores at 12 months. CONCLUSIONS: Individuals with early, substantial increases in brain amyloid experience poor outcomes in the form of memory dysfunction and heightened symptoms (memory deficits, headaches, difficulty concentrating, etc.) at 12 months post-injury. Data presented here suggests that florbetapir F18 PET imaging may be a sensitive biomarker for predicting outcomes within the mild and moderate TBI population.