The role of autophagy in Nmnat-mediated protection against hypoxia-induced dendrite degeneration

Yuhui Wen, Rong G Zhai, Michael D. Kim

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

The selective degeneration of dendrites precedes neuronal cell death in hypoxia-ischemia (HI) and is a neuropathological hallmark of stroke. While it is clear that a number of different molecular pathways likely contribute to neuronal cell death in HI, the mechanisms that govern HI-induced dendrite degeneration are largely unknown. Here, we show that the NAD synthase nicotinamide mononucleotide adenylyltransferase (Nmnat) functions endogenously to protect Drosophila class IV dendritic arborization (da) sensory neurons against hypoxia-induced dendritic damage. Whereas dendrites of wild-type class IV neurons are largely resistant to morphological changes during prolonged periods of hypoxia (<1.0% O2), class IV neurons of nmnat heterozygous mutants exhibit significant dendrite loss and extensive fragmentation of the dendritic arbor under the same hypoxic conditions. Although basal levels of autophagy are required for neuronal survival, we demonstrate that autophagy is dispensable for maintaining the dendritic integrity of class IV neurons. However, we find that genetically blocking autophagy can suppress hypoxia-induced dendrite degeneration of nmnat heterozygous mutants in a cell-autonomous manner, suggestive of a self-destructive role for autophagy in this context. We further show that inducing autophagy by overexpression of the autophagy-specific kinase Atg1 is sufficient to cause dendrite degeneration of class IV neurons under hypoxia and that overexpression of Nmnat fails to protect class IV dendrites from the effects of Atg1 overexpression. Our studies reveal an essential neuroprotective role for endogenous Nmnat in hypoxia and demonstrate that Nmnat functions upstream of autophagy to mitigate the damage incurred by dendrites in neurons under hypoxic stress.

Original languageEnglish
Pages (from-to)140-151
Number of pages12
JournalMolecular and Cellular Neuroscience
Volume52
DOIs
StatePublished - Jan 1 2013

Fingerprint

Nicotinamide-Nucleotide Adenylyltransferase
Autophagy
Dendrites
Neurons
Ischemia
Cell Death
Neuronal Plasticity
Hypoxia
Sensory Receptor Cells
Drosophila
Phosphotransferases
Stroke

Keywords

  • Autophagy
  • Dendrite
  • Drosophila
  • Hypoxia-ischemia
  • Neurodegeneration
  • Nmnat

ASJC Scopus subject areas

  • Molecular Biology
  • Cellular and Molecular Neuroscience
  • Cell Biology

Cite this

The role of autophagy in Nmnat-mediated protection against hypoxia-induced dendrite degeneration. / Wen, Yuhui; Zhai, Rong G; Kim, Michael D.

In: Molecular and Cellular Neuroscience, Vol. 52, 01.01.2013, p. 140-151.

Research output: Contribution to journalArticle

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