title: Mitochondrial impairment in the cerebellum of the patients with progressive supranuclear palsy.
abstract: Abnormalities in energy metabolism and oxidative stress accompany many neurodegenerative diseases, including progressive supranuclear palsy (PSP). Previously, we showed decreased activities of a mitochondrial enzyme complex, alpha-ketoglutarate dehydrogenase complex (KGDHC), and marked increases in tissue malondialdehyde levels in post-mortem superior frontal cortex from the patients with PSP. The current study demonstrates that KGDHC is also significantly diminished (-58%) in the cerebellum from patients with PSP (n = 14), compared to age-matched control brains (n = 13). In contrast to cortex, markers of oxidative stress, such as malondialdehyde, tyrosine nitration or general protein carbonyl modification, did not increase in cerebellum. Furthermore, the protein levels of the individual components of KGDHC did not decline. The activities of two other mitochondrial enzymes were measured to determine whether the changes in KGDHC were selective. The activity of aconitase, a mitochondrial enzyme with an iron/sulfur cluster, is also significantly diminished (-50%), whereas glutamate dehydrogenase activity is unchanged. The present results suggest that the interaction of metabolic impairment and oxidative stress is region-specific in PSP brain. In cerebellum, reductions in KGDHC occur in the absence of increases in common measures of oxidative stress, and may underlie the metabolic deficits and contribute to pathological and clinical manifestation related to the cerebellum in patients with PSP.
authors.affiliation: Department of Neurology and Neuroscience, Weill Medical College of Cornell University, 785 Mamaroneck Avenue, White Plains, NY 10605, USA.
authors.forename: L C
authors.initials: LC
authors.lastname: Park
authors.forename: D S
authors.initials: DS
authors.lastname: Albers
authors.forename: H
authors.initials: H
authors.lastname: Xu
authors.forename: J G
authors.initials: JG
authors.lastname: Lindsay
authors.forename: M F
authors.initials: MF
authors.lastname: Beal
authors.forename: G E
authors.initials: GE
authors.lastname: Gibson
mesh_terms: D000154:Aconitate Hydratase / Q000378:metabolism; D000818:Animals; D001928:Brain Diseases, Metabolic / Q000201:enzymology / Q000503:physiopathology; D002531:Cerebellum / Q000201:enzymology* / Q000503:physiopathology; D015536:Down-Regulation / Q000502:physiology*; D004734:Energy Metabolism / Q000502:physiology*; D005969:Glutamate Dehydrogenase / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D007655:Ketoglutarate Dehydrogenase Complex / Q000378:metabolism*; D051379:Mice; D008928:Mitochondria / Q000201:enzymology* / Q000473:pathology; D028361:Mitochondrial Diseases / Q000201:enzymology / Q000503:physiopathology; D009569:Nitric Oxide / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology*; D013347:Subcellular Fractions / Q000378:metabolism; D013494:Supranuclear Palsy, Progressive / Q000201:enzymology* / Q000503:physiopathology; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism
chemical_list: D009569:Nitric Oxide; C002744:3-nitrotyrosine; D014443:Tyrosine; D007655:Ketoglutarate Dehydrogenase Complex; D005969:Glutamate Dehydrogenase; D000154:Aconitate Hydratase