A vesicular sequestration to oxidative deamination shift in myocardial sympathetic nerves in Parkinson's disease.
In Parkinson's disease (PD), profound putamen dopamine (DA) depletion reflects denervation and a shift from vesicular sequestration to oxidative deamination of cytoplasmic DA in residual terminals. PD also involves cardiac sympathetic denervation. Whether PD entails myocardial norepinephrine (NE) depletion and a sequestration-deamination shift have been unknown. We measured apical myocardial tissue concentrations of NE, DA, and their neuronal metabolites 3,4-dihydroxyphenylglycol (DHPG), and 3,4-dihydroxyphenylacetic acid (DOPAC) from 23 PD patients and 23 controls and ascertained the extent of myocardial NE depletion in PD. We devised, validated in VMAT2-Lo mice, and applied 5 neurochemical indices of the sequestration-deamination shift-concentration ratios of DOPAC:DA, DA:NE, DHPG:NE, DOPAC:NE, and DHPG:DOPAC-and used a kinetic model to estimate the extent of the vesicular storage defect. The PD group had decreased myocardial NE content (p < 0.0001). The majority of patients (70%) had severe NE depletion (mean 2% of control), and in this subgroup all five indices of a sequestration-deamination shift were increased compared to controls (p < 0.001 for each). Vesicular storage in residual nerves was estimated to be decreased by 84-91% in this subgroup. We conclude that most PD patients have severe myocardial NE depletion, because of both sympathetic denervation and decreased vesicular storage in residual nerves. We found that the majority (70%) of Parkinson's disease (PD) patients have profound (98%) myocardial norepinephrine depletion, because of both cardiac sympathetic denervation and a shift from vesicular sequestration to oxidative deamination of cytoplasmic catecholamines in the residual nerves. This shift may be part of a final common pathogenetic pathway in the loss of catecholaminergic neurons that characterizes PD.
Clinical Neurocardiology Section, CNP/DIR/NINDS/NIH, Bethesda, Maryland, USA.
David S
DS
Goldstein
Clinical Neurocardiology Section, CNP/DIR/NINDS/NIH, Bethesda, Maryland, USA.
Patricia
P
Sullivan
Clinical Neurocardiology Section, CNP/DIR/NINDS/NIH, Bethesda, Maryland, USA.
Courtney
C
Holmes
School of Public Health, Environmental Health, Emory University, Atlanta, Georgia, USA.
Gary W
GW
Miller
Hypertension Unit, Chaim Sheba Medical Center, and Tel Aviv University, Tel-HaShomer, Israel.
Yehonatan
Y
Sharabi
Clinical Neurocardiology Section, CNP/DIR/NINDS/NIH, Bethesda, Maryland, USA.
Irwin J
IJ
Kopin
D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D003641:Deamination / Q000502:physiology; D004298:Dopamine / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D009638:Norepinephrine / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology*; D010300:Parkinson Disease / Q000378:metabolism* / Q000473:pathology; D017779:Sympathetic Fibers, Postganglionic / Q000378:metabolism* / Q000473:pathology; D013572:Synaptic Vesicles / Q000378:metabolism*; D050493:Vesicular Monoamine Transport Proteins / Q000172:deficiency / Q000378:metabolism
C493453:Slc18a2 protein, mouse; D050493:Vesicular Monoamine Transport Proteins; D004298:Dopamine; D009638:Norepinephrine
Parkinson's disease; catecholamines; neurochemistry; neurodegenerative mechanisms; sympathetic nervous system