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Mol Neurobiol. 2019 Mar;56(3):2007-2021. doi: 10.1007/s12035-018-1218-2. Epub 2018 Jul 7.

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

Author information

1
Department of Neurology, Seoul National University Hospital, Seoul, South Korea.
2
Biomedical Research Institute, Seoul National University Hospital, Seoul, South Korea.
3
Department of Biomedical Sciences, Korea University College of Medicine, Seoul, South Korea.
4
Department of Neurology, Seoul National University Seoul Metropolitan Government Boramae Medical Center, Seoul, South Korea.
5
Department of Neurology, Seoul National University Hospital, Seoul, South Korea. jjsaint@snu.ac.kr.
6
Neuroscience Research Institute, Seoul National University College of Medicine, Seoul, South Korea. jjsaint@snu.ac.kr.

Abstract

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.

KEYWORDS:

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

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