Cellular Zn2+ chelators cause "dying-back" neurite degeneration associated with energy impairment

Yi Yang, Taku Kawataki, Koji Fukui, Tatsuro Koike

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Most cellular zinc is tightly associated with metalloproteins and other Zn2+-dependent proteins, which along with cellular Zn2+ compartments may coordinately regulate cytoplasmic free Zn2+ levels in the picomolar range. Moreover, Zn2+-containing endosomes or protein complexes appear to move along axons or dendrites, suggesting a dynamic mechanism for trafficking, exchanging, or scavenging Zn2+ and/or Zn2+ protein complexes in neurons. It is therefore interesting to examine whether cellular Zn2+ levels might alter neurite integrity and dynamics. Here we show that membrane-permeable zinc chelators, including 1,10-phenanthroline, N,N,N′,N′-tetrakis-(2-pyridylmethyl)- ethylenediamine (TPEN), and zinquin, selectively elicit axon and dendrite degeneration but leave the cell body intact in sympathetic neurons. The process begins distally and then moves retrogradely, with a distinct "dying-back" pattern. An inactive isomer of 1,10-phenanthroline failed to cause neuite degeneration, and these chelators mediated their effects by selectively chelating Zn2+, but not other metals. Moreover, neurite degeneration was associated with a decrease in neuritic ATP levels and was caused by energy failure, because an exogenous supply of nicotinamide adenine dinucleotide (NAD) or its precursor nicotinamide suppressed the degeneration by delaying axonal ATP reduction caused by Zn2+ depletion. Blockage of autophagy by 3-methyladenine provided partial protection against degeneration of terminal axons or dendrites; there was, however, no obvious alteration in that of medial portions. Collectively, our results show that cellular Zn2+ depletion induces a "dying-back" degeneration characterized by an NAD- and autophagy-dependent process, independently of neurite elongation dynamics.

Original languageEnglish
Pages (from-to)2844-2855
Number of pages12
JournalJournal of Neuroscience Research
Volume85
Issue number13
DOIs
Publication statusPublished - 2007 Oct
Externally publishedYes

Keywords

  • Autophagy
  • Axon degeneration
  • Mitochondria
  • NAD
  • Sympathetic neuron

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Cellular Zn2+ chelators cause "dying-back" neurite degeneration associated with energy impairment. / Yang, Yi; Kawataki, Taku; Fukui, Koji; Koike, Tatsuro.

In: Journal of Neuroscience Research, Vol. 85, No. 13, 10.2007, p. 2844-2855.

Research output: Contribution to journalArticle

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