title: Reduced vesicular storage of dopamine causes progressive nigrostriatal neurodegeneration.
abstract: The vesicular monoamine transporter 2 (VMAT2; SLC18A2) is responsible for packaging dopamine into vesicles for subsequent release and has been suggested to serve a neuroprotective role in the dopamine system. Here, we show that mice that express approximately 5% of normal VMAT2 (VMAT2 LO) display age-associated nigrostriatal dopamine dysfunction that ultimately results in neurodegeneration. Elevated cysteinyl adducts to L-DOPA and DOPAC are seen early and are followed by increased striatal protein carbonyl and 3-nitrotyrosine formation. These changes were associated with decreased striatal dopamine and decreased expression of the dopamine transporter and tyrosine hydroxylase. Furthermore, we observed an increase in alpha-synuclein immunoreactivity and accumulation and neurodegeneration in the substantia nigra pars compacta in aged VMAT2 LO mice. Thus, VMAT2 LO animals display nigrostriatal degeneration that begins in the terminal fields and progresses to eventual loss of the cell bodies, alpha-synuclein accumulation, and an L-DOPA responsive behavioral deficit, replicating many of the key aspects of Parkinson's disease. These data suggest that mishandling of dopamine via reduced VMAT2 expression is, in and of itself, sufficient to cause dopamine-mediated toxicity and neurodegeneration in the nigrostriatal dopamine system. In addition, the altered dopamine homeostasis resulting from reduced VMAT2 function may be conducive to pathogenic mechanisms induced by genetic or environmental factors thought to be involved in Parkinson's disease.
authors.affiliation: Center for Neurodegenerative Disease, Rollins School of Public Health, Emory University, Atlanta, Georgia 30322, USA.
authors.forename: W Michael
authors.initials: WM
authors.lastname: Caudle
authors.forename: Jason R
authors.initials: JR
authors.lastname: Richardson
authors.forename: Min Z
authors.initials: MZ
authors.lastname: Wang
authors.forename: Tonya N
authors.initials: TN
authors.lastname: Taylor
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Guillot
authors.forename: Alison L
authors.initials: AL
authors.lastname: McCormack
authors.forename: Rebecca E
authors.initials: RE
authors.lastname: Colebrooke
authors.forename: Donato A
authors.initials: DA
authors.lastname: Di Monte
authors.forename: Piers C
authors.initials: PC
authors.lastname: Emson
authors.forename: Gary W
authors.initials: GW
authors.lastname: Miller
mesh_terms: D000818:Animals; D004298:Dopamine / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017072:Neostriatum / Q000378:metabolism* / Q000473:pathology; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D013378:Substantia Nigra / Q000378:metabolism* / Q000473:pathology; D013572:Synaptic Vesicles / Q000235:genetics / Q000378:metabolism*; D050493:Vesicular Monoamine Transport Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: C493453:Slc18a2 protein, mouse; D050493:Vesicular Monoamine Transport Proteins; D004298:Dopamine