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Impaired Cytoplasmic–Nuclear Transport of Hypoxia‐Inducible Factor‐1α in Amyotrophic Lateral Sclerosis
Authors:Yuko Nagara  Takahisa Tateishi  Ryo Yamasaki  Shintaro Hayashi  Mami Kawamura  Hitoshi Kikuchi  Kyoko Motomura Iinuma  Masahito Tanaka  Toru Iwaki  Takuya Matsushita  Yasumasa Ohyagi  Jun‐ichi Kira
Affiliation:1. Department of Neurology, Kyushu University, , Fukuoka, Japan;2. Department of Neuropathology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, , Fukuoka, Japan
Abstract:
We investigated the mechanisms underlying abnormal vascular endothelial growth factor (VEGF) production in amyotrophic lateral sclerosis (ALS). We immunohistochemically studied VEGF, its receptors VEGFR1 and 2, and hypoxia‐inducible factor‐1α (HIF‐1α) in autopsied ALS spinal cords. We also chronologically assessed the expression of HIF‐1α, karyopherin β1, karyopherin β‐cargo protein complex inhibitors and nuclear pore complex proteins in G93A mutant superoxide dismutase 1 (mSOD1) transgenic mice at presymptomatic, symptomatic and end stages. In ALS patients, compared with controls, HIF‐1α immunoreactivity in the cytoplasm of anterior horn cells (AHCs) was significantly increased, while immunoreactivities for VEGF and VEGFRs were significantly decreased. Similar changes in HIF‐1α and VEGF levels were observed in mSOD1 transgenic mice. HIF‐1α co‐localized with karyopherin β1 in the cytoplasm of AHCs and karyopherin β1 co‐localized with nucleoporin 62 (Nup62) on the nuclear envelope. From the presymptomatic stage of mSOD1 transgenic mice, karyopherin β1 immunoreactivity in AHC nuclei significantly decreased and morphological irregularities of the Nup62‐immunostained nuclear envelope became more pronounced with disease progression. Thus, in AHCs from mSOD1 transgenic mice, transport of cytoplasmic HIF‐1α to the nuclear envelope and into the nucleus is impaired from the presymptomatic stage, suggesting that impaired cytoplasmic–nuclear transport of HIF‐1α through the nuclear pore might precede motor neuron degeneration.
Keywords:amyotrophic lateral sclerosis  hypoxia‐inducible factor‐1α    impaired cytoplasmic–  nuclear transport  mutant superoxide dismutase 1  vascular endothelial growth factor
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