Impaired cytoplasmic-nuclear transport of hypoxia-inducible factor-1α in amyotrophic lateral sclerosis.
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.
Department of Neurology, Kyushu University, Fukuoka 812-8582, Japan.
Yuko
Y
Nagara
Takahisa
T
Tateishi
Ryo
R
Yamasaki
Shintaro
S
Hayashi
Mami
M
Kawamura
Hitoshi
H
Kikuchi
Kyoko Motomura
KM
Iinuma
Masahito
M
Tanaka
Toru
T
Iwaki
Takuya
T
Matsushita
Yasumasa
Y
Ohyagi
Jun-ichi
J
Kira
D021581:Active Transport, Cell Nucleus; D000368:Aged; D000369:Aged, 80 and over; D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D000818:Animals; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000378:metabolism; D028861:Nuclear Pore Complex Proteins / Q000378:metabolism; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology; D013482:Superoxide Dismutase / Q000235:genetics; D000072105:Superoxide Dismutase-1; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism; D028961:beta Karyopherins / Q000378:metabolism
D005904:Glial Fibrillary Acidic Protein; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C424166:KPNB1 protein, human; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; D028861:Nuclear Pore Complex Proteins; C000606290:SOD1 protein, human; D042461:Vascular Endothelial Growth Factor A; D028961:beta Karyopherins; C049312:nuclear pore protein p62; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2; D010751:Phosphopyruvate Hydratase
amyotrophic lateral sclerosis; hypoxia-inducible factor-1α; impaired cytoplasmic-nuclear transport; mutant superoxide dismutase 1; vascular endothelial growth factor