Brain tissue from normal individuals with incidental Lewy bodies and cell loss in pigmented substantia nigra neurons (asymptomatic Parkinson's disease) and age-matched control subjects without nigral Lewy bodies was examined biochemically. There was no difference in dopamine levels or dopamine turnover in the caudate and putamen of individuals with incidental Lewy body disease compared to control subjects. There were no differences in levels of iron, copper, manganese, or zinc in the substantia nigra or other brain regions from the individuals with incidental Lewy body disease compared to those from control subjects. Similarly, ferritin levels in the substantia nigra and other brain areas were unaltered. There was no difference in the activity of succinate cytochrome c reductase (complexes II and III) or cytochrome oxidase (complex IV) between incidental Lewy body subjects and control subjects. Rotenone-sensitive NADH coenzyme Q1 reductase activity (complex I) was reduced to levels intermediate between those in control subjects and those in patients with overt Parkinson's disease, but this change did not reach statistical significance. The levels of reduced glutathione in substantia nigra were reduced by 35% in patients with incidental Lewy body disease compared to control subjects. Reduced glutathione levels in other brain regions were unaffected and there were no changes in oxidized glutathione levels in any brain region. Altered iron metabolism is not detectable in the early stages of nigral dopamine cell degeneration. There may be some impairment of mitochondrial complex I activity in the substantia nigra in Parkinson's disease.(ABSTRACT TRUNCATED AT 250 WORDS)
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From the Montreal Neurological Institute and Department of Neurology and Neurosurgery (R.P.), Montréal, McGill University; Center for Advanced Research in Sleep Medicine (R.P., A.P., J.-F.G.), Hôpital du Sacré-Coeur de Montréal; Research Institute of the McGill University Health Centre (R.P., A.P., Z.G.-O.), Montreal, Quebec, Canada; Neurology and Medicine (N.V., L.K.F., J.A.F., O.A.R., W.S., B.F.B., A.M.), Mayo Clinic, Rochester, MN; Division of Neurology (N.V., E.K.S.L.), Department of Medicine, Faculty of Medicine, Khon Kaen University, Thailand; Department of Neurology (M.M.L., J.E.), Oregon Health & Science University; Department of Behavioral Neuroscience (M.M.L.); Department of Pulmonary and Critical Care Medicine; Oregon Institute of Occupational Health Sciences; Mental Illness Research Education and Clinical Center (M.M.L.); Neurology; National Center for Rehabilitative Auditory Research; Research Service (M.M.L., J.E.), VA Portland Health Care System, OR; Département of Psychology (J.-F.G.), Université du Québec à Montréal; Department of Human Genetics (Z.G.-O.), McGill University, Montréal, Québec, Canada; Neurology (D.E.H., D.L.B.), Emory University, Atlanta, GA; Neurology (A.Y.A.), Sleep Disorders Center, University of California, Los Angeles; Minnesota Regional Sleep Disorders Center (M.H., C.H.S.), and Departments of Psychiatry, Hennepin County Medical Center, and University of Minnesota Medical School; Minnesota Regional Sleep Disorders Center (M.H.), Hennepin County Medical Center, Minneapolis, MN; Washington University School of Medicine (J.M., A.A.D., Y.-E.S.J.), Saint Louis, MO; Barrow Neurological Institute (S.R.C.), Phoenix, AZ; Movement Disorders Unit (A.V.), Division of Sleep Medicine, Massachusetts General Hospital; Neurological Clinical Research Institute (A.V.), Harvard Medical School, Boston, MA; Psychiatry and Behavioral Sciences (E.H.D., M.G.M.), Stanford University, Redwood City, CA; Neurology and Neurological Sciences (E.H.D., M.G.M.), Stanford University, Palo Alto, CA; and Neurology (E.H.D.), Mt. Sinai School of Medicine, New York.
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Alpha-synuclein (αsyn) is the key pathogenic protein implicated in synucleinopathies including Parkinson's Disease (PD) and Dementia with Lewy Bodies (DLB). In these diseases, αsyn is thought to spread between cells where it accumulates and induces pathology; however, mechanisms that drive its propagation or aggregation are poorly understood. We have previously reported that the small GTPase Rab27b is elevated in human PD and DLB and that it can mediate the autophagic clearance and toxicity of αsyn in a paracrine αsyn cell culture neuronal model.
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Acta Neuropathol
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Section Clinical Neuroanatomy and Biobanking, Department of Anatomy and Neurosciences, Amsterdam UMC, Vrije University, Amsterdam, The Netherlands.
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