Increased protein hydrophobicity in response to aging and Alzheimer disease |
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| Authors: | Kalavathi Dasuri Philip Ebenezer Le Zhang Sun Ok Fernandez-Kim Annadora J Bruce-Keller William R Markesbery Jeffrey N Keller |
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| Institution: | 1. Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA 70808, USA;2. Department of Pathology and Laboratory Medicine and Department of Neurology, Sanders–Brown Center on Aging, and Alzheimer''s Disease Center, University of Kentucky College of Medicine, Lexington, KY 40506, USA;1. Center for Engineering Training, China Jiliang University, Hangzhou 310018, China;2. Institute of Thermal Engineering, China Jiliang University, Hangzhou 310018, China;1. Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy;2. Department of Neurology, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy;3. Clinic of Neurology, School of Medicine, University of Belgrade, Belgrade, Serbia;1. Department of Biological Sciences, Carnegie Mellon University, United States;2. Computational Biology Department, Carnegie Mellon University, United States;1. Cancer and Inflammation Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA;2. Sackler Inst. of Molecular Medicine, Department of Human Genetics and Molecular Medicine, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel |
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| Abstract: | Increased levels of misfolded and damaged proteins occur in response to brain aging and Alzheimer disease (AD), which presumably increase the amount of aggregation-prone proteins via elevations in hydrophobicity. The proteasome is an intracellular protease that degrades oxidized and ubiquitinated proteins, and its function is known to be impaired in response to both aging and AD. In this study we sought to determine the potential for increased levels of protein hydrophobicity occurring in response to aging and AD, to identify the contribution of proteasome inhibition to increased protein hydrophobicity, and last to identify the contribution of ubiquitinated and oxidized proteins to the pool of hydrophobic proteins. In our studies we identified that aging and AD brain exhibited increases in protein hydrophobicity as detected using Bis ANS, with dietary restriction (DR) significantly decreasing age-related increases in protein hydrophobicity. Affinity chromatography purification of hydrophobic proteins from aging and AD brains identified increased levels of oxidized and ubiquitinated proteins in the pool of hydrophobic proteins. Pharmacological inhibition of the proteasome in neurons, but not astrocytes, resulted in an increase in protein hydrophobicity. Taken together, these data indicate that there is a relationship between increased protein oxidation and protein ubiquitination and elevations in protein hydrophobicity within the aging and the AD brain, which may be mediated in part by impaired proteasome activity in neurons. Our studies also suggest a potential role for decreased oxidized and hydrophobic proteins in mediating the beneficial effects of DR. |
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