J Clin Neurol.  2019 Jan;15(1):62-67. 10.3988/jcn.2019.15.1.62.

Impaired Nucleoporins Are Present in Sporadic Amyotrophic Lateral Sclerosis Motor Neurons that Exhibit Mislocalization of the 43-kDa TAR DNA-Binding Protein

Affiliations
  • 1Department of Neurology, Tokyo Medical University, Tokyo, Japan. haizawa@tokyo-med.ac.jp
  • 2Division of Clinical Biotechnology, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
  • 3Department of Neurology, Asahikawa Medical Center, National Hospital Organization, Asahikawa, Japan.

Abstract

BACKGROUND AND PURPOSE
Disruption of nucleoporins has been reported in the motor neurons of patients with sporadic amyotrophic lateral sclerosis (sALS). However, the precise changes in the morphology of nucleoporins associated with the pathology of the 43-kDa TAR DNA-binding protein (TDP-43) in the disease process remain unknown. We investigated the expression of nucleoporins that constitute the nuclear pore complex (NPC) in spinal motor neurons that exhibit sALS in relation to TDP-43 pathology, which is a reliable neuropathological hallmark of sALS.
METHODS
Paraffin-embedded sections of the lumbar spinal cord were obtained for immunofluorescence analysis from seven control subjects and six sALS patients. Anti-TDP-43 antibody, anti-nucleoporin p62 (NUP62) antibody, and anti-karyopherin beta 1 (KPNB1) antibody were applied as primary antibodies, and then visualized using appropriate secondary antibodies. The sections were then examined under a fluorescence microscope.
RESULTS
NUP62 and KPNB1 immunoreactivity appeared as a smooth round rim bordering the nuclear margin in normal spinal motor neurons that exhibited nuclear TDP-43 immunoreactivity. sALS spinal motor neurons with apparent TDP-43 mislocalization demonstrated irregular, disrupted nuclear staining for NUP62 or KPNB1. Some atrophic sALS spinal motor neurons with TDP-43 mislocalization presented no NUP62 immunoreactivity.
CONCLUSIONS
Our findings suggest a close relationship between NPC alterations and TDP-43 pathology in the degenerative process of the motor neurons of sALS patients.

Keyword

sporadic amyotrophic lateral sclerosis; nucleoporin; nuclear pore complex; 43-kDa TAR DNA-binding protein

MeSH Terms

Amyotrophic Lateral Sclerosis*
Antibodies
Fluorescence
Fluorescent Antibody Technique
Humans
Motor Neurons*
Nuclear Pore
Nuclear Pore Complex Proteins*
Pathology
Spinal Cord
Antibodies
Nuclear Pore Complex Proteins
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