BACKGROUND Lewy body diseases, a family of aging-related neurodegenerative disorders, entail loss of the catecholamine dopamine in the nigrostriatal system and equally severe deficiency of the closely related catecholamine norepinephrine in the heart. The myocardial noradrenergic lesion is associated with major nonmotor symptoms and decreased survival. Numerous mechanisms determine norepinephrine stores, and which of these are altered in Lewy body diseases has not been examined in an integrated way. We used a computational modeling approach to assess comprehensively pathways of cardiac norepinephrine synthesis, storage, release, reuptake, and metabolism in Lewy body diseases. Application of a potentially novel kinetic model identified a pattern of dysfunctional steps contributing to norepinephrine deficiency. We then tested predictions from the model in a new cohort of Parkinson disease patients.METHODS Rate constants were calculated for 17 reactions determining intraneuronal norepinephrine stores. Model predictions were tested by measuring postmortem apical ventricular concentrations and concentration ratios of catechols in controls and patients with Parkinson disease.RESULTS The model identified low rate constants for 3 types of processes in the Lewy body group: catecholamine biosynthesis via tyrosine hydroxylase and aromatic l-amino acid decarboxylase, vesicular storage of dopamine and norepinephrine, and neuronal norepinephrine reuptake via the cell membrane norepinephrine transporter. Postmortem catechols and catechol ratios confirmed this triad of model-predicted functional abnormalities.CONCLUSION Denervation-independent impairments of neurotransmitter biosynthesis, vesicular sequestration, and norepinephrine recycling contribute to the myocardial norepinephrine deficiency attending Lewy body diseases. A proportion of cardiac sympathetic nerves are “sick but not dead,” suggesting targeted disease modification strategies might retard clinical progression.FUNDING Division of Intramural Research, NINDS.
David S. Goldstein, Mark J. Pekker, Graeme Eisenhofer, Yehonatan Sharabi
Title and authors | Publication | Year |
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The Catecholaldehyde Hypothesis for the Pathogenesis of Catecholaminergic Neurodegeneration: What We Know and What We Do Not Know
DS Goldstein |
International journal of molecular sciences | 2021 |
Cardiac tyrosine hydroxylase activation and MB-COMT in dyskinetic monkeys
L Cuenca-Bermejo, P Almela, P Gallo-Soljancic, JE Yuste, V de Pablos, V Bautista-Hernández, E Fernández-Villalba, ML Laorden, MT Herrero |
Scientific Reports | 2021 |
Dynamic planar scintigraphy for the rapid kinetic measurement of myocardial 123I-MIBG turnover can identify Lewy body disease
Y Kumakura, Y Shimizu, M Hariu, K Ichikawa, N Yoshida, M Suzuki, S Oji, S Narukawa, H Yoshimasu, K Nomura |
EJNMMI Research | 2021 |
Differential Susceptibilities of Catecholamines to Metabolism by Monoamine Oxidases
Goldstein DS, Castillo G, Sullivan P, Sharabi Y |
The Journal of pharmacology and experimental therapeutics | 2021 |