title: Implications for oxidative stress and astrocytes following 26S proteasomal depletion in mouse forebrain neurones.
abstract: Neurodegenerative diseases are characterized by progressive degeneration of selective neurones in the nervous system, but the underlying mechanisms involved in neuroprotection and neurodegeneration remain unclear. Dysfunction of the ubiquitin proteasome system is one of the proposed hypotheses for the cause and progression of neuronal loss. We have performed quantitative two-dimensional fluorescence difference in-gel electrophoresis combined with peptide mass fingerprinting to reveal proteome changes associated with neurodegeneration following 26S proteasomal depletion in mouse forebrain neurones. Differentially expressed proteins were validated by Western blotting, biochemical assays and immunohistochemistry. Of significance was increased expression of the antioxidant enzyme peroxiredoxin 6 (PRDX6) in astrocytes, associated with oxidative stress. Interestingly, PRDX6 is a bifunctional enzyme with antioxidant peroxidase and phospholipase A2 (PLA2) activities. The PLA2 activity of PRDX6 was also increased following 26S proteasomal depletion and may be involved in neuroprotective or neurodegenerative mechanisms. This is the first in vivo report of oxidative stress caused directly by neuronal proteasome dysfunction in the mammalian brain. The results contribute to understanding neuronal-glial interactions in disease pathogenesis, provide an in vivo link between prominent disease hypotheses and importantly, are of relevance to a heterogeneous spectrum of neurodegenerative diseases.
authors.affiliation: School of Biomedical Sciences, University of Nottingham, Nottingham, UK.
authors.forename: Jamal
authors.initials: J
authors.lastname: Elkharaz
authors.forename: Aslihan
authors.initials: A
authors.lastname: Ugun-Klusek
authors.forename: Dumitru
authors.initials: D
authors.lastname: Constantin-Teodosiu
authors.forename: Karen
authors.initials: K
authors.lastname: Lawler
authors.forename: R John
authors.initials: RJ
authors.lastname: Mayer
authors.forename: Ellen
authors.initials: E
authors.lastname: Billett
authors.forename: James
authors.initials: J
authors.lastname: Lowe
authors.forename: Lynn
authors.initials: L
authors.lastname: Bedford
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism* / Q000473:pathology; D015153:Blotting, Western; D015180:Electrophoresis, Gel, Two-Dimensional; D007124:Immunoenzyme Techniques; D015227:Lipid Peroxidation; D051379:Mice; D009410:Nerve Degeneration / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress; D054467:Phospholipases A2 / Q000378:metabolism; D016548:Prosencephalon / Q000378:metabolism* / Q000473:pathology; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
chemical_list: D017382:Reactive Oxygen Species; D054467:Phospholipases A2; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease
keywords: 26S proteasome; Astrocytes; Neurodegeneration; Oxidative stress; Peroxiredoxin 6; Ubiquitin proteasome system