title: Deficient vesicular storage: A common theme in catecholaminergic neurodegeneration.
abstract: Several neurodegenerative diseases involve loss of catecholamine neurons--Parkinson's disease (PD) is a prototypical example. Catecholamine neurons are rare in the nervous system, and why they are lost has been mysterious. Accumulating evidence supports the concept of "autotoxicity"--inherent cytotoxicity caused by catecholamine metabolites. Since vesicular sequestration limits the buildup of toxic products of enzymatic and spontaneous oxidation of catecholamines, a vesicular storage defect could play a pathogenic role in the death of catecholaminergic neurons in a variety of neurodegenerative diseases. In putamen, deficient vesicular storage is revealed in vivo by accelerated loss of (18)F-DOPA-derived radioactivity and post-mortem by decreased tissue dopamine (DA):DOPA ratios; in myocardium in vivo by accelerated loss of (18)F-dopamine-derived radioactivity and post-mortem by increased 3,4-dihydroxyphenylglycol:norepinephrine (DHPG:NE) ratios; and in sympathetic noradrenergic nerves overall in vivo by increased plasma F-dihydroxyphenylacetic acid (F-DOPAC):DHPG ratios. We retrospectively analyzed data from 20 conditions with decreased or intact catecholaminergic innervation, involving different etiologies, pathogenetic mechanisms, and lesion locations. All conditions involving parkinsonism had accelerated loss of putamen (18)F-DOPA-derived radioactivity; in those with post-mortem data there were also decreased putamen DA:DOPA ratios. All conditions involving cardiac sympathetic denervation had accelerated loss of myocardial (18)F-dopamine-derived radioactivity; in those with post-mortem data there were increased myocardial DHPG:NE ratios. All conditions involving localized loss of catecholaminergic innervation had evidence of decreased vesicular storage specifically in the denervated regions. Thus, across neurodegenerative diseases, loss of catecholaminergic neurons seems to be associated with decreased vesicular storage in the residual neurons.
authors.affiliation: Clinical Neurocardiology Section, Clinical Neurosciences Program, Division of Intramural Research, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, 20892, 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, National Institutes of Health, Bethesda, MD, 20892, 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, National Institutes of Health, Bethesda, MD, 20892, USA.
authors.forename: Patti
authors.initials: P
authors.lastname: Sullivan
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
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
authors.forename: Ellen
authors.initials: E
authors.lastname: Sidransky
authors.affiliation: Movement Disorder Center, University of Tor Vergata, Rome, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Stefani
authors.affiliation: Clinical Neurocardiology Section, Clinical Neurosciences Program, Division of Intramural Research, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, 20892, 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 School of Medicine, Tel-Avid, Israel.
authors.forename: Yehonatan
authors.initials: Y
authors.lastname: Sharabi
mesh_terms: D001344:Autopsy; D002395:Catecholamines / Q000378:metabolism*; D019788:Fluorodeoxyglucose F18 / Q000378:metabolism; D006801:Humans; D007980:Levodopa / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000378:metabolism* / Q000473:pathology*; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D010300:Parkinson Disease / Q000378:metabolism / Q000473:pathology; D011699:Putamen / Q000473:pathology*; D013572:Synaptic Vesicles / Q000378:metabolism*
chemical_list: D002395:Catecholamines; D019788:Fluorodeoxyglucose F18; D007980:Levodopa
keywords: Catecholamine; Dopamine; Neurodegeneration; Norepinephrine; Parkinson's disease