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The inhibition of TDP-43 mitochondrial localization blocks its neuronal toxicity

Nature Medicine volume 22, pages 869–878 (2016)Cite this article

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Abstract

Genetic mutations in TAR DNA-binding protein 43 (TARDBP, also known as TDP-43) cause amyotrophic lateral sclerosis (ALS), and an increase in the presence of TDP-43 (encoded by TARDBP) in the cytoplasm is a prominent histopathological feature of degenerating neurons in various neurodegenerative diseases. However, the molecular mechanisms by which TDP-43 contributes to ALS pathophysiology remain elusive. Here we have found that TDP-43 accumulates in the mitochondria of neurons in subjects with ALS or frontotemporal dementia (FTD). Disease-associated mutations increase TDP-43 mitochondrial localization. In mitochondria, wild-type (WT) and mutant TDP-43 preferentially bind mitochondria-transcribed messenger RNAs (mRNAs) encoding respiratory complex I subunits ND3 and ND6, impair their expression and specifically cause complex I disassembly. The suppression of TDP-43 mitochondrial localization abolishes WT and mutant TDP-43-induced mitochondrial dysfunction and neuronal loss, and improves phenotypes of transgenic mutant TDP-43 mice. Thus, our studies link TDP-43 toxicity directly to mitochondrial bioenergetics and propose the targeting of TDP-43 mitochondrial localization as a promising therapeutic approach for neurodegeneration.

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Figure 1: TDP-43 co-localizes with and accumulates in mitochondria in individuals with ALS and FTD.
Figure 2: ALS-associated genetic mutations in TDP-43 increase its import into mitochondria.
Figure 3: TDP-43 mitochondrial import depends on internal M1, M3 and M5 motifs.
Figure 4: TDP-43 preferentially binds mitochondria-transcribed ND3 and ND6 mRNAs and inhibits their translation.
Figure 5: TDP-43 specifically reduces complex I assembly and impairs mitochondrial function and morphology.
Figure 6: Suppression of TDP-43 mitochondrial localization abolishes TDP-43 neurotoxicity.

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Acknowledgements

This study is supported by grants from the US National Institutes of Health (R03AG044680 and 1R01NS089604 to X.W.), the US Alzheimer's Association (2014-NIRG-301299 to X.W.) and the University Hospitals of Cleveland, USA (2012 SPITZ Innovation Pilot Grant to X.W.). Human spinal cord frozen tissues were obtained from the Eunice Kennedy Shriver National Institute of Child Health and Human Development Brain and Tissue Bank for Developmental Disorders at the University of Maryland, Baltimore, Maryland, USA, contract HHSN275200900011C, ref. no. N01-HD-9-0011. We also thank G. Perry and X. Zhu for providing paraffin-embedded human spinal cord tissues.

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Author notes

  1. Wenzhang Wang, Luwen Wang and Junjie Lu: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pathology, Case Western Reserve University, Cleveland, Ohio, USA

    Wenzhang Wang, Luwen Wang, Sandra L Siedlak, Sirui Jiang, Xiaopin Ma, Zhen Jiang, Max Sheng, Heewon Choi & Xinglong Wang

  2. Department of Pediatric Newborn Medicine, Brigham & Women's Hospital, Boston, Massachusetts, USA

    Junjie Lu

  3. Electron Microscopy Core Facility, Case Western Reserve University, Cleveland, Ohio, USA

    Hisashi Fujioka

  4. Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio, USA

    Jingjing Liang

  5. Department of Molecular Pharmacology & Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota, USA

    Edroaldo Lummertz da Rocha & Hu Li

  6. Department of Pediatrics, Massachusetts General Hospital, Boston, Massachusetts, USA

    Paul H Lerou

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  1. Wenzhang Wang
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Contributions

X.W. conceived and directed the project, interpreted results and wrote the manuscript. W.W., L.W., J.L., S.L.S., J.L., S.J., X.M., Z.J., M.S., H.C. and X.W. contributed to experiments, data analysis and manuscript preparation. H.F. contributed to electron microscopy study. E.L.D.R. and H.L. contributed to RNA-seq study. P.H.L. contributed to the reprogramming of human fibroblasts into human neurons.

Corresponding author

Correspondence to Xinglong Wang.

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Competing interests

X.W. has a patent pending regarding peptides inhibiting TDP-43 mitochondrial localization.

Supplementary information

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Supplementary Figures 1–12 and Supplementary Tables 1–3 (PDF 19349 kb)

Supplementary Video 1

Representative movie of NTG mice treated with cPM. (AVI 14378 kb)

Supplementary Video 2

Representative movie of TG mice treated with cPM. (AVI 9077 kb)

Supplementary Video 3

Representative movie of TG mice treated with PM1. (AVI 25014 kb)

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Wang, W., Wang, L., Lu, J. et al. The inhibition of TDP-43 mitochondrial localization blocks its neuronal toxicity. Nat Med 22, 869–878 (2016). https://doi.org/10.1038/nm.4130

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