title: Decreased vesicular storage and aldehyde dehydrogenase activity in multiple system atrophy.
abstract: BACKGROUND
  Parkinson disease (PD) and multiple system atrophy (MSA) share some neuropathologic features (nigrostriatal dopaminergic lesion, alpha-synuclein deposition) but not others (Lewy bodies in PD, glial cytoplasmic inclusions in MSA). In PD evidence has accrued for a vesicular storage defect and decreased aldehyde dehydrogenase (ALDH) activity in residual dopaminergic terminals, resulting in accumulation of the toxic dopamine (DA) metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL). In this study we asked whether MSA entails a similar abnormal neurochemical pattern.
  
  
  METHODS
  DA and its main neuronal metabolite 3,4-dihydroxyphenylacetic acid (DOPAC), norepinephrine (NE) and its main neuronal metabolite 3,4-dihydroxyphenylglycol (DHPG), the catecholamine precursor DOPA, and DOPAL were measured in striatal and frontal cortical tissue from patients with pathologically proven end-stage MSA (N = 15), sporadic PD (N = 17), and control subjects (N = 18).
  
  
  RESULTS
  Compared to the control group, the MSA and PD groups had similarly decreased putamen DA (by 96% and 93%, p < 0.0001), DOPAC (97% and 95%, p < 0.0001), NE (91% and 74%, p < 0.0001), and DHPG (81% and 74%, p < 0.0001). In the MSA and PD groups, ratios of DOPAL:DA were 2.3 and 3.5 times control and DHPG:NE 3.1 and 2.6 times control, while DOPAC:DOPAL ratios were decreased by 61% and 74%. In both diseases cortical NE and DHPG were decreased, while DA and DOPAC were not.
  
  
  CONCLUSIONS
  MSA and PD entail a catecholamine metabolic profile indicating impaired vesicular storage, decreased ALDH activity, and DOPAL buildup, which might be part of a common pathway in catecholamine neuronal death. Targeting this pathway by interfering with catecholaldehyde production or effects constitutes a novel treatment approach.
authors.affiliation: Clinical Neurocardiology Section, Clinical Neurosciences Program, Division of Intramural Research, National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA. Electronic address: goldsteind@ninds.nih.gov.
authors.forename: David S
authors.initials: DS
authors.lastname: Goldstein
authors.affiliation: Clinical Neurocardiology Section, Clinical Neurosciences Program, Division of Intramural Research, National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA.
authors.forename: Patricia
authors.initials: P
authors.lastname: Sullivan
authors.affiliation: Clinical Neurocardiology Section, Clinical Neurosciences Program, Division of Intramural Research, National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA.
authors.forename: Courtney
authors.initials: C
authors.lastname: Holmes
authors.affiliation: Clinical Neurocardiology Section, Clinical Neurosciences Program, Division of Intramural Research, National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA.
authors.forename: Irwin J
authors.initials: IJ
authors.lastname: Kopin
authors.affiliation: Department of Internal Medicine, Chaim Sheba Medical Center, Tel-HaShomer, and Sackler Faculty of Medicine, Tel-Aviv University, Israel.
authors.forename: Yehonatan
authors.initials: Y
authors.lastname: Sharabi
authors.affiliation: Department of Neurology, Miller School of Medicine, University of Miami, Miami, FL, USA.
authors.forename: Deborah C
authors.initials: DC
authors.lastname: Mash
mesh_terms: D015102:3,4-Dihydroxyphenylacetic Acid / Q000031:analogs & derivatives / Q000378:metabolism; D000368:Aged; D000369:Aged, 80 and over; D000444:Aldehyde Dehydrogenase / Q000378:metabolism*; D003342:Corpus Striatum / Q000378:metabolism*; D004295:Dihydroxyphenylalanine / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D005260:Female; D005625:Frontal Lobe / Q000378:metabolism*; D006801:Humans; D008297:Male; D008734:Methoxyhydroxyphenylglycol / Q000031:analogs & derivatives / Q000378:metabolism; D019578:Multiple System Atrophy / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism; D010300:Parkinson Disease / Q000378:metabolism*
chemical_list: D015102:3,4-Dihydroxyphenylacetic Acid; D008734:Methoxyhydroxyphenylglycol; C007430:3,4-dihydroxyphenylacetaldehyde; D004295:Dihydroxyphenylalanine; D000444:Aldehyde Dehydrogenase; C010117:3,4-dihydroxyphenylglycol; D004298:Dopamine; D009638:Norepinephrine
keywords: DOPAL; Dopamine; Multiple system atrophy; Norepinephrine; Parkinson disease; Putamen
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