Aberrant distributions of nuclear pore complex proteins in ALS mice and ALS patients. (14th May 2017)

• Record Type: Journal Article
• Authors: Shang, Jingwei; Yamashita, Toru; Nakano, Yumiko; Morihara, Ryuta; Li, Xianghong; Feng, Tian; Liu, Xia; Huang, Yong; Fukui, Yusuke; Hishikawa, Nozomi; Ohta, Yasuyuki; Abe, Koji
• Is Part Of: Neuroscience. Volume 350(2017)
• Page Start: 158
• Page End: 168
• Publication Date: 2017-05-14
• Subjects: ALS amyotrophic lateral sclerosis -- C9-ALS C9orf72 amyotrophic lateral sclerosis -- DAPI 4′, 6-diamidino-2-phenylindole -- G4C2 GGGGCC -- GP210 nuclear pore glycoprotein-210 -- NCT neucleocytoplasmic transport -- NE nuclear envelope -- NPCs nuclear pore complexes -- NUP107 nucleoporin 107 -- NUP205 nucleoporin 205 -- NUP50 nucleoporin 50 -- PBS phosphate-buffered saline -- PFA paraformaldehyde -- RanGAP1 Ran GTPase-activating protein 1 -- SOD1 hours (h), human superoxide dismutase-1 -- SOD1-Tg human superoxide dismutase-1 transgenic -- TDP43 transactivation response DNA binding protein 43 -- Tg transgenic -- W weeks -- WT wild type; aberrant distribution -- amyotrophic lateral sclerosis -- human superoxide dismutase-1 transgenic mice -- nuclear pore complexes -- nucleoporin; Neurochemistry -- Periodicals; Neurophysiology -- Periodicals; Neurology -- Periodicals; Neurochimie -- Périodiques; Neurophysiologie -- Périodiques; Neurochemistry; Neurophysiology; Electronic journals; Periodicals; Electronic journals; 612.8
• DOI: 10.1016/j.neuroscience.2017.03.024
• Languages: English
• ISSNs: 0306-4522

Abstract

Graphical abstract: Highlights: Spatiotemporal expressions of nucleoporins in SOD1-Tg mice and ALS patients. Nucleoporins and TDP43 are co-localized in ALS. Nucleoporin dysfunctions are not specific only in C9-ALS but also in SOD1-ALS mice. Abstract: Nuclear pore complexes (NPCs) play important roles in traffic of molecules between the nucleus and cytoplasm, aberrant distributions of components of NPCs were demonstrated in C9orf72 amyotrophic lateral sclerosis (C9-ALS) patients, but it is elusive whether such abnormities are also the case with other cause of ALS disease. In the present study, we investigated the spatiotemporal distributions of RanGAP1 and 4 representative nucleoporins (GP210, NUP205, NUP107 and NUP50) of NPCs in human Cu/Zn superoxide dismutase-1 mutation transgenic (SOD1-Tg) mice and sporadic ALS patients. Compared with wild type (WT), these proteins displayed age-dependent and progressive nuclear precipitations, and cytoplasmic aberrant expressions in motor neurons of lumbar cord in SOD1-Tg mice from 10 to 18 weeks (W). Double immunofluorescent analysis showed abnormal nuclear retention and apparent co-localizations of RanGAPl with NUP205 and NUP205 with NUPl07, meanwhile, GP210 with NUP205 mainly co-localized in the nuclear envelope (NE) of motor neurons. Furthermore, RanGAP1, GP210 and NUP50 showed similarly abnormal nuclear precipitations and cytoplasmic upregulations in SOD1-Tg mice and ALS patients, moreover, aberrant co-localizations of RanGAP1 with TDP-43 and NUP205 with TDP-43 were also observed in motor neurons. The present study indicated that the mislocalization of these proteins of NPCs may underlie the pathogenesis of ALS both in SOD1-Tg mice and human sporadic ALS patients, and these dysfunctions may be a fundamental pathway for ALS that is not specific only in C9-ALS but also in SOD1-ALS, which may be amenable to pharmacotherapeutic intervention.