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Phosphorylated and aggregated TDP-43 with seeding properties are induced upon mutant Huntingtin (mHtt) polyglutamine expression in human cellular models

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Abstract

The Tar DNA-Binding Protein 43 (TDP-43) and its phosphorylated isoform (pTDP-43) are the major components associated with ubiquitin positive/Tau-negative inclusions found in neurons and glial cells of patients suffering of amyotrophic lateral sclerosis (ALS) or frontotemporal lobar degeneration-TDP-43 (FTLD–TDP). Many studies have revealed that TDP-43 is also in the protein inclusions associated with neurodegenerative conditions other than ALS and FTLD–TDP, thus suggesting that this protein may be involved in the pathogenesis of a variety of neurological disorders. In brains of Huntington-affected patients, pTDP-43 aggregates were shown to co-localize with mutant Huntingtin (mHtt) inclusions. Here, we show that expression of mHtt carrying 80–97 polyglutamines repeats in human cell cultures induces the aggregation and the phosphorylation of endogenous TDP-43, whereas non-pathological Htt with 25 polyglutamines repeats has no effect. Mutant Htt aggregation precedes accumulation of pTDP-43 and pTDP-43 co-localizes with mHtt inclusions reminding what it was previously described in brains of Huntington-affected patients. Detergent-insoluble fractions from cells expressing mHtt and containing mHtt–pTDP-43 co-aggregates can function as seeds for further TDP-43 aggregation in human cell culture. The human cellular prion protein PrPC was previously identified as a negative modulator of mHtt aggregation; here, we show that PrPC-mediated reduction of mHtt aggregation is tightly correlated with a decrease of TDP-43 aggregation and phosphorylation, thus confirming the close relationships between TDP-43 and mHtt.

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Acknowledgements

This work was supported by the CNRS and the INSERM (PL), and Grant-in-Aid for Scientific Research on Innovative Areas (Brain Protein Aging and Dementia Control) (JP26117005) from MEXT (to M.H.), a Grant-in-Aid for Scientific Research on Brain Mapping by Integrated Neurotechnologies for Disease Studies (Brain/MINDS) (JP14533254) from AMED (to M.H.), JST CREST Grant number JP18071300, Japan, and a Grant from Brain Science Foundation (to T.N.). PL received the support of the Association pour la recherche sur la SLA (ARSLA), the NeuroDis Fundation and the AFM (AFM-MyoNeuralp). LC received for his PhD an ARC2 “Qualité de vie et Viellissement” Grant from the région Auvergne Rhône-Alpes. We thank Didier Vilette (ENVT–Toulouse) for carefully reading the manuscript and helpful discussions. We acknowledge the LYMIC-PLATIM and the CIQLE microscope platforms at ENS Lyon (SFR Biosciences Gerland–Lyon Sud UMS3444/US8, France) and at the Faculté de médecine Rockefeller (Lyon Est, France) respectively.

Author information

Author notes

  1. Laurent Coudert and Takashi Nonaka contributed equally.

Authors and Affiliations

  1. Institut NeuroMyoGène, CNRS UMR5310, INSERM U1217, Faculté de Médecine Rockefeller, Université Claude Bernard Lyon I, 8 Avenue Rockefeller, 69373, Lyon Cedex 08, France

    Laurent Coudert, Laurent Schaeffer & Pascal Leblanc

  2. Dementia Research Project, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo, 156-8506, Japan

    Takashi Nonaka & Masato Hasegawa

  3. Hospices Civils de Lyon, Hôpital Neurologique Pierre-Wertheimer, Service de Neurologie C et Centre SLA de Lyon, Bron, France

    Emilien Bernard

  4. Université de Lyon, Faculté de Médecine Lyon Sud Charles Mérieux, Lyon, France

    Emilien Bernard

Authors
  1. Laurent Coudert
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  2. Takashi Nonaka
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  3. Emilien Bernard
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  4. Masato Hasegawa
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  5. Laurent Schaeffer
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  6. Pascal Leblanc
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Contributions

TN, LC and PL conducted the experiments. All the authors interpreted the data and corrected the paper. PL wrote the manuscript.

Corresponding author

Correspondence to Pascal Leblanc.

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The authors declare that they have no competing interests.

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Coudert, L., Nonaka, T., Bernard, E. et al. Phosphorylated and aggregated TDP-43 with seeding properties are induced upon mutant Huntingtin (mHtt) polyglutamine expression in human cellular models. Cell. Mol. Life Sci. 76, 2615–2632 (2019). https://doi.org/10.1007/s00018-019-03059-8

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  • DOI: https://doi.org/10.1007/s00018-019-03059-8

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