Premium
A vesicular sequestration to oxidative deamination shift in myocardial sympathetic nerves in Parkinson's disease
Author(s) -
Goldstein David S.,
Sullivan Patricia,
Holmes Courtney,
Miller Gary W.,
Sharabi Yehonatan,
Kopin Irwin J.
Publication year - 2014
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.12766
Subject(s) - norepinephrine , denervation , medicine , parkinson's disease , chemistry , dopamine , endocrinology , deamination , biochemistry , disease , enzyme
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 VMAT 2‐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.