Pathological Modification of TDP-43 in Amyotrophic Lateral Sclerosis with SOD1 Mutations

Gye Sun Jeon, Yu Mi Shim, Do Yeon Lee, Jun Soon Kim, Min Jin Kang, So Hyun Ahn, Je Young Shin, Dongho Geum, Yoon Ho Hong, Jung Joon Sung

Research output: Contribution to journalArticlepeer-review

45 Citations (Scopus)


Amyotrophic lateral sclerosis (ALS) is a fatal, adult-onset, progressive neurodegenerative disorder with no known cure. Cu/Zn-superoxide dismutase (SOD1) was the first identified protein associated with familial ALS (fALS). Recently, TAR DNA-binding protein 43 (TDP-43) has been found to be a principal component of ubiquitinated cytoplasmic inclusions in neurons and glia in ALS. However, it remains unclear whether these ALS-linked proteins partly have a shared pathogenesis. Here, we determine the association between mutant SOD1 and the modification of TDP-43 and the relationship of pathologic TDP-43 to neuronal cytotoxicity in SOD1 ALS. In this work, using animal model, human tissue, and cell models, we provide the evidence that the association between the TDP-43 modification and the pathogenesis of SOD1 fALS. We demonstrated an age-dependent increase in TDP-43 C-terminal fragments and phosphorylation in motor neurons and glia of SOD1 mice and SOD1G85S ALS patient. Cytoplasmic TDP-43 was also observed in iPSC-derived motor neurons from SOD1G17S ALS patient. Moreover, we observed that mutant SOD1 interacts with TDP-43 in co-immunoprecipitation assays with G93A hSOD1-transfected cell lines. Mutant SOD1 overexpression led to an increase in TDP-43 modification in the detergent-insoluble fraction in the spinal cord of SOD1 mice and fALS patient. Additionally, we showed cellular apoptosis in response to the interaction of mutant SOD1 and fragment forms of TDP-43. These findings suggest that mutant SOD1 could affect the solubility/insolubility of TDP-43 through physical interactions and the resulting pathological modifications of TDP-43 may be involved in motor neuron death in SOD1 fALS.

Original languageEnglish
Pages (from-to)2007-2021
Number of pages15
JournalMolecular Neurobiology
Issue number3
Publication statusPublished - 2019 Mar 1

Bibliographical note

Funding Information:
Flag-tagged TDP-43, TDP-35, and TDP-25 vector, provided by Hong-Yu Hu, Chinese Academy of Sciences, Shanghai, China.

Funding Information:
Funding Information This study was supported by Grants from the SNUH Research Fund (03-2014-0370) and from the Korea Healthcare Technology R&D Project, Ministry of health and Welfare, Republic of Korea (HI14C3347).

Publisher Copyright:
© 2018, The Author(s).


  • Amyotrophic lateral sclerosis (ALS)
  • Glial cells
  • Mutant SOD1
  • TAR DNA binding protein (TDP-43)

ASJC Scopus subject areas

  • Neurology
  • Cellular and Molecular Neuroscience


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