Impaired cytoplasmic-nuclear transport of hypoxia-inducible factor-1α in amyotrophic lateral sclerosis

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

研究成果: ジャーナルへの寄稿記事

28 引用 (Scopus)

抄録

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.

元の言語英語
ページ(範囲)534-546
ページ数13
ジャーナルBrain Pathology
23
発行部数5
DOI
出版物ステータス出版済み - 9 1 2013

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Hypoxia-Inducible Factor 1
Cell Nucleus Active Transport
Amyotrophic Lateral Sclerosis
Karyopherins
Anterior Horn Cells
Nuclear Pore Complex Proteins
Transgenic Mice
Nuclear Envelope
Vascular Endothelial Growth Factor A
Cytoplasm
Nuclear Pore
Nerve Degeneration
Vascular Endothelial Growth Factor Receptor
Motor Neurons
Cell Nucleus
Disease Progression
Spinal Cord
Superoxide Dismutase-1

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)
  • Pathology and Forensic Medicine
  • Clinical Neurology

これを引用

Impaired cytoplasmic-nuclear transport of hypoxia-inducible factor-1α in amyotrophic lateral sclerosis. / Nagara, Yuko; Tateishi, Takahisa; Yamasaki, Ryo; Hayashi, Shintaro; Kawamura, Mami; Kikuchi, Hitoshi; Iinuma, Kyoko Motomura; Tanaka, Masahito; Iwaki, Toru; Matsushita, Takuya; Ohyagi, Yasumasa; Kira, Jun-Ichi.

:: Brain Pathology, 巻 23, 番号 5, 01.09.2013, p. 534-546.

研究成果: ジャーナルへの寄稿記事

Nagara, Y, Tateishi, T, Yamasaki, R, Hayashi, S, Kawamura, M, Kikuchi, H, Iinuma, KM, Tanaka, M, Iwaki, T, Matsushita, T, Ohyagi, Y & Kira, J-I 2013, 'Impaired cytoplasmic-nuclear transport of hypoxia-inducible factor-1α in amyotrophic lateral sclerosis', Brain Pathology, 巻. 23, 番号 5, pp. 534-546. https://doi.org/10.1111/bpa.12040
Nagara, Yuko ; Tateishi, Takahisa ; Yamasaki, Ryo ; Hayashi, Shintaro ; Kawamura, Mami ; Kikuchi, Hitoshi ; Iinuma, Kyoko Motomura ; Tanaka, Masahito ; Iwaki, Toru ; Matsushita, Takuya ; Ohyagi, Yasumasa ; Kira, Jun-Ichi. / Impaired cytoplasmic-nuclear transport of hypoxia-inducible factor-1α in amyotrophic lateral sclerosis. :: Brain Pathology. 2013 ; 巻 23, 番号 5. pp. 534-546.
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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.",
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AU - Kawamura, Mami

AU - Kikuchi, Hitoshi

AU - Iinuma, Kyoko Motomura

AU - Tanaka, Masahito

AU - Iwaki, Toru

AU - Matsushita, Takuya

AU - Ohyagi, Yasumasa

AU - Kira, Jun-Ichi

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AB - 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.

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