title: Reduced vesicular storage of catecholamines causes progressive degeneration in the locus ceruleus.
abstract: Parkinson's disease (PD) is the most common neurodegenerative motor disease. Pathologically, PD is characterized by Lewy body deposition and subsequent death of dopamine neurons in the substantia nigra pars compacta. PD also consistently features degeneration of the locus ceruleus, the main source of norepinephrine in the central nervous system. We have previously reported a mouse model of dopaminergic neurodegeneration based on reduced expression of the vesicular monoamine transporter (VMAT2 LO). To determine if reduced vesicular storage can also cause noradrenergic degeneration, we examined indices of damage to the catecholaminergic systems in brain and cardiac tissue of VMAT2 LO mice. At two months of age, neurochemical analyses revealed substantial reductions in striatal dopamine (94%), cortical dopamine (57%) and norepinephrine (54%), as well as cardiac norepinephrine (97%). These losses were accompanied by increased conversion of dopamine and norepinephrine to their deaminated metabolites. VMAT2 LO mice exhibited loss of noradrenergic innervation in the cortex, as determined by norepinephrine transporter immunoreactivity and (3)H-nisoxetine binding. Using unbiased stereological techniques, we observed progressive degeneration in the locus ceruleus that preceded degeneration of the substantia nigra pars compacta. In contrast, the ventral tegmental area, which is spared in human PD, remained unaffected. The coordinate loss of dopamine and norepinephrine neurons in VMAT2 LO mice parallels the pattern of neurodegeneration that occurs in human PD, and demonstrates that insufficient catecholamine storage can cause spontaneous degeneration in susceptible neurons, underscoring cytosolic catecholamine catabolism as a determinant of neuronal susceptibility in PD. This article is part of the Special Issue entitled 'The Synaptic Basis of Neurodegenerative Disorders'.
authors.affiliation: Center for Neurodegenerative Disease, Atlanta, GA, USA; Department of Environmental Health, Emory University, Atlanta, GA, USA.
authors.forename: Tonya N
authors.initials: TN
authors.lastname: Taylor
authors.forename: Shawn P
authors.initials: SP
authors.lastname: Alter
authors.forename: Minzheng
authors.initials: M
authors.lastname: Wang
authors.forename: David S
authors.initials: DS
authors.lastname: Goldstein
authors.forename: Gary W
authors.initials: GW
authors.lastname: Miller
mesh_terms: D000818:Animals; D002395:Catecholamines / Q000378:metabolism*; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology; D003342:Corpus Striatum / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D005260:Female; D008125:Locus Coeruleus / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D051379:Mice; D008818:Mice, Neurologic Mutants; D009206:Myocardium / Q000378:metabolism; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009638:Norepinephrine / Q000378:metabolism; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000378:metabolism; D010300:Parkinson Disease / Q000378:metabolism / Q000473:pathology; D050493:Vesicular Monoamine Transport Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D002395:Catecholamines; D050484:Norepinephrine Plasma Membrane Transport Proteins; C493453:Slc18a2 protein, mouse; D050493:Vesicular Monoamine Transport Proteins; D004298:Dopamine; D009638:Norepinephrine
keywords: 3,4-dihydroxyphenylacetaldehyde; 3,4-dihydroxyphenylacetic acid; 3,4-dihydroxyphenylglycol; 3-4-dihydroxyphenylglycolaldehyde; DA; DHPG; DOPAC; DOPAL; DOPEGAL; LC; Locus ceruleus; MAO; NE; NET; Norepinephrine; Parkinson's disease; SNpc; TH; VMAT2; VTA; dopamine; locus ceruleus; monoamine oxidase; norepinephrine; norepinephrine transporter; substantia nigra pars compacta; tyrosine hydroxylase; ventral tegmental area; vesicular monoamine transporter 2
references.citation: Acta Neuropathol. 2008 Feb;115(2):193-203
references.pmid: 17965867
references.citation: J Neurol Neurosurg Psychiatry. 2013 Jul;84(7):774-83
references.pmid: 23064099
references.citation: Neurobiol Aging. 2003 Mar-Apr;24(2):197-211
references.pmid: 12498954
references.citation: J Neuropathol Exp Neurol. 1996 Mar;55(3):259-72
references.pmid: 8786384
references.citation: Parkinsons Dis. 2011 Feb 21;2011:124165
references.pmid: 21403896
references.citation: Mol Cell Biol. 2001 Aug;21(16):5321-31
references.pmid: 11463816
references.citation: Neurobiol Aging. 2008 Nov;29(11):1702-11
references.pmid: 17582657
references.citation: Brain Pathol. 2005 Jan;15(1):29-34
references.pmid: 15779234
references.citation: J Neurol. 2002 Oct;249 Suppl 3:III/1-5
references.pmid: 12528692
references.citation: Mov Disord. 2013 Jun;28(6):715-24
references.pmid: 23589357
references.citation: Biochem Pharmacol. 2007 Jul 15;74(2):177-90
references.pmid: 17416354
references.citation: Brain Res. 1990 Feb 26;510(1):104-7
references.pmid: 1691042
references.citation: J Neurosci. 1994 Apr;14(4):2260-71
references.pmid: 8158268
references.citation: J Neurosci. 2009 Jun 24;29(25):8103-13
references.pmid: 19553450
references.citation: Anat Rec. 1991 Dec;231(4):482-97
references.pmid: 1793176
references.citation: Curr Opin Neurobiol. 2005 Jun;15(3):312-8
references.pmid: 15916893
references.citation: Clin Auton Res. 2007 Apr;17(2):118-21
references.pmid: 17334896
references.citation: BMC Neurosci. 2001;2:11
references.pmid: 11591219
references.citation: Proc Natl Acad Sci U S A. 1997 Sep 2;94(18):9938-43
references.pmid: 9275230
references.citation: Eur J Neurol. 2011 May;18(5):703-10
references.pmid: 21073636
references.citation: Mech Ageing Dev. 1983 Sep;23(1):73-94
references.pmid: 6228698
references.citation: J Neurosci. 2012 May 2;32(18):6072-80
references.pmid: 22553014
references.citation: J Neuropathol Exp Neurol. 1991 Nov;50(6):743-55
references.pmid: 1748881
references.citation: Neurobiol Aging. 2013 Jun;34(6):1712.e9-13
references.pmid: 23369548
references.citation: Science. 1977 Feb 18;195(4279):646-53
references.pmid: 841304
references.citation: Exp Neurol. 1998 Apr;150(2):339-42
references.pmid: 9527905
references.citation: Toxicol Sci. 2006 Aug;92(2):490-9
references.pmid: 16702228
references.citation: Hum Mol Genet. 2006 Jan 15;15(2):299-305
references.pmid: 16339215
references.citation: Lancet Neurol. 2003 Nov;2(11):669-76
references.pmid: 14572735
references.citation: Neuron. 2009 Apr 30;62(2):163-4
references.pmid: 19409260
references.citation: Mt Sinai J Med. 2011 Nov-Dec;78(6):872-81
references.pmid: 22069211
references.citation: J Comp Neurol. 1989 Sep 15;287(3):357-72
references.pmid: 2570793
references.citation: Science. 2001 Nov 9;294(5545):1346-9
references.pmid: 11701929
references.citation: Neurobiol Dis. 2012 Sep;47(3):367-77
references.pmid: 22659302
references.citation: Trends Neurosci. 2008 Jun;31(6):303-8
references.pmid: 18471904
references.citation: Ann Neurol. 1997 Apr;41(4):530-9
references.pmid: 9124811
references.citation: Neurotoxicology. 2012 Oct;33(5):1298-304
references.pmid: 22906799
references.citation: FASEB J. 2000 Dec;14(15):2459-65
references.pmid: 11099463
references.citation: Neurotoxicology. 2004 Jan;25(1-2):101-15
references.pmid: 14697885
references.citation: Neurosci Biobehav Rev. 2000 Aug;24(6):655-68
references.pmid: 10940440
references.citation: J Neuropsychiatry Clin Neurosci. 2001 Spring;13(2):222-8
references.pmid: 11449029
references.citation: J Neurochem. 2008 Sep;106(5):2205-17
references.pmid: 18643795
references.citation: Eur J Neurosci. 2006 Nov;24(9):2622-30
references.pmid: 17100850
references.citation: Nat Med. 2001 Dec;7(12):1280-2
references.pmid: 11726961
references.citation: Neuron. 1997 Dec;19(6):1285-96
references.pmid: 9427251
references.citation: Exp Neurol. 1999 Mar;156(1):138-48
references.pmid: 10192785
references.citation: Parkinsonism Relat Disord. 2011 Dec;17(10):724-9
references.pmid: 21571570
references.citation: J Clin Invest. 2011 Aug;121(8):3320-30
references.pmid: 21785221
references.citation: Neurotox Res. 2000 Feb;1(3):181-95
references.pmid: 12835101
references.citation: J Pharmacol Exp Ther. 1992 Jan;260(1):427-36
references.pmid: 1731049
references.citation: Neuron. 2003 Sep 11;39(6):889-909
references.pmid: 12971891
references.citation: Ann N Y Acad Sci. 1992 May 11;648:42-62
references.pmid: 1353337
references.citation: J Neurochem. 2013 Sep;126(5):591-603
references.pmid: 23786406
references.citation: J Nucl Cardiol. 1994 Mar-Apr;1(2 Pt 2):S23-30
references.pmid: 9420694
references.citation: Arch Neurol. 2003 Mar;60(3):337-41
references.pmid: 12633144
references.citation: J Chromatogr B Biomed Appl. 1994 Mar 4;653(2):131-8
references.pmid: 8205240
references.citation: J Neurosci. 2007 Jul 25;27(30):8138-48
references.pmid: 17652604
references.citation: Neuron. 2009 Apr 30;62(2):218-29
references.pmid: 19409267