Deficient vesicular storage: A common theme in catecholaminergic neurodegeneration

David S. Goldstein, Courtney Holmes, Patti Sullivan, Deborah C. Mash, Ellen Sidransky, Alessandro Stefani, Irwin J. Kopin, Yehonatan Sharabi

Research output: Contribution to journalShort survey

15 Scopus citations

Abstract

Several neurodegenerative diseases involve loss of catecholamine neurons-Parkinson's disease (PD) is a prototypical example. Catecholamine neurons are rare in the nervous system, and why they are lost has been mysterious. Accumulating evidence supports the concept of "autotoxicity"-inherent cytotoxicity caused by catecholamine metabolites. Since vesicular sequestration limits the buildup of toxic products of enzymatic and spontaneous oxidation of catecholamines, a vesicular storage defect could play a pathogenic role in the death of catecholaminergic neurons in a variety of neurodegenerative diseases. In putamen, deficient vesicular storage is revealed in vivo by accelerated loss of 18F-DOPA-derived radioactivity and post-mortem by decreased tissue dopamine (DA):DOPA ratios; in myocardium in vivo by accelerated loss of 18F-dopamine-derived radioactivity and post-mortem by increased 3,4-dihydroxyphenylglycol:norepinephrine (DHPG:NE) ratios; and in sympathetic noradrenergic nerves overall in vivo by increased plasma F-dihydroxyphenylacetic acid (F-DOPAC):DHPG ratios. We retrospectively analyzed data from 20 conditions with decreased or intact catecholaminergic innervation, involving different etiologies, pathogenetic mechanisms, and lesion locations. All conditions involving parkinsonism had accelerated loss of putamen 18F-DOPA-derived radioactivity; in those with post-mortem data there were also decreased putamen DA:DOPA ratios. All conditions involving cardiac sympathetic denervation had accelerated loss of myocardial 18F-dopamine-derived radioactivity; in those with post-mortem data there were increased myocardial DHPG:NE ratios. All conditions involving localized loss of catecholaminergic innervation had evidence of decreased vesicular storage specifically in the denervated regions. Thus, across neurodegenerative diseases, loss of catecholaminergic neurons seems to be associated with decreased vesicular storage in the residual neurons.

Original languageEnglish (US)
Pages (from-to)1013-1022
Number of pages10
JournalParkinsonism and Related Disorders
Volume21
Issue number9
DOIs
StatePublished - Sep 1 2015

Keywords

  • Catecholamine
  • Dopamine
  • Neurodegeneration
  • Norepinephrine
  • Parkinson's disease

ASJC Scopus subject areas

  • Neurology
  • Geriatrics and Gerontology
  • Clinical Neurology

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    Goldstein, D. S., Holmes, C., Sullivan, P., Mash, D. C., Sidransky, E., Stefani, A., Kopin, I. J., & Sharabi, Y. (2015). Deficient vesicular storage: A common theme in catecholaminergic neurodegeneration. Parkinsonism and Related Disorders, 21(9), 1013-1022. https://doi.org/10.1016/j.parkreldis.2015.07.009