Impaired Cytoplasmic-Nuclear Transport of Hypoxia-Inducible Factor-1α in Amyotrophic Lateral Sclerosis

• Published in: Brain pathology (Zurich, Switzerland) Switzerland), 2013-09, Vol.23 (5), p.534-546
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Active Transport, Cell Nucleus; Aged; Aged, 80 and over; amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - metabolism; Amyotrophic Lateral Sclerosis - pathology; Amyotrophic Lateral Sclerosis - physiopathology; Animals; beta Karyopherins - metabolism; Female; Gene Expression Regulation - genetics; Glial Fibrillary Acidic Protein - metabolism; Humans; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; hypoxia-inducible factor-1α; impaired cytoplasmic-nuclear transport; Male; Membrane Glycoproteins - metabolism; Mice; Mice, Transgenic; Middle Aged; mutant superoxide dismutase 1; Mutation - genetics; Nerve Tissue Proteins - metabolism; Nuclear Pore Complex Proteins - metabolism; Phosphopyruvate Hydratase - metabolism; Spinal Cord - metabolism; Spinal Cord - pathology; Superoxide Dismutase - genetics; Superoxide Dismutase-1; vascular endothelial growth factor; Vascular Endothelial Growth Factor A - metabolism; Vascular Endothelial Growth Factor Receptor-1 - genetics; Vascular Endothelial Growth Factor Receptor-1 - metabolism; Vascular Endothelial Growth Factor Receptor-2 - genetics; Vascular Endothelial Growth Factor Receptor-2 - metabolism
• ISSN: 1015-6305; 1750-3639
• DOI: 10.1111/bpa.12040

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.