Impaired response of hypoxic sensor protein HIF-1α and its downstream proteins in the spinal motor neurons of ALS model mice

Kota Sato, Nobutoshi Morimoto, Tomoko Kurata, Takafumi Mimoto, Kazunori Miyazaki, Yoshio Ikeda, Koji Abe

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

We have recently reported spinal blood flow-metabolism uncoupling in an amyotrophic lateral sclerosis (ALS) animal model using Cu/Zn-superoxide dismutase 1 (SOD1)-transgenic (Tg) mice, suggesting a relative hypoxia in the spinal cord. However, the hypoxic stress sensor pathway has not been well studied in ALS. Here, we examined temporal and spatial changes of the hypoxic stress sensor proteins HIF-1α and its downstream proteins (VEGF, HO-1, and EPO) during the normoxiccourse of motor neuron (MN) degeneration in the spinal cord of these ALS model mice. We found that HIF-1α protein expression progressively increased both in the anterior large MNs and the surrounding glial cells in Tg mice from early symptomatic 14 week (W) and end stage 18 W. Double immunofluorescence analysis revealed that HIF-1α, plus GFAP and Iba-1 double-positive surrounding glial cells, progressively increased from 14 W to 18 W, although the immunohistochemistry in large MNs did not change. Expression levels of VEGF and HO-1 also showed a progressive increase but were significant only in the surrounding glial cells at 18 W. In contrast, EPO protein expression was decreased in the surrounding glial cells of Tg mice at 18 W. Because HIF1-α serves as an important mediator of the hypoxic response, these findings indicate that MNs lack the neuroprotective response to hypoxic stress through the HIF-1α system, which could be an important mechanism of neurodegeneration in ALS.

Original languageEnglish
Pages (from-to)55-62
Number of pages8
JournalBrain Research
Volume1473
DOIs
Publication statusPublished - Sep 14 2012

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Keywords

  • ALS
  • EPO
  • HIF-1α
  • HO-1
  • VEGF

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Clinical Neurology
  • Developmental Biology

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