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Pathogenic Ubqln2 gains toxic properties to induce neuron death

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Abstract

Mutations in ubiquilin 2 (Ubqln2) is linked to amyotrophic lateral sclerosis and frontotemporal lobar degeneration. A foremost question regarding Ubqln2 pathogenesis is whether pathogenically mutated Ubqln2 causes neuron death via a gain or loss of functions. To better understand Ubqln2 pathobiology, we created Ubqln2 transgenic and knockout rats and compared phenotypic expression in these novel rat models. Overexpression of Ubqln2 with a pathogenic mutation (P497H substitution) caused cognitive deficits and neuronal loss in transgenic rats at the age of 130 days. In the transgenic rats, neuronal loss was preceded by the progressive formation of Ubqln2 aggregates and was accompanied by the progressive accumulation of the autophagy substrates p62 and LC3-II and the impairment of endosome pathways. In contrast, none of these pathologies observed in mutant Ubqln2 transgenic rats was detected in Ubqln2 knockout rats at the age of 300 days. Together, our findings in Ubqln2 transgenic and knockout rats collectively suggest that pathogenic Ubqln2 causes neuron death mainly through a gain of unrevealed functions rather than a loss of physiological functions.

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Acknowledgments

This work is supported by the National Institutes of Health (NIH)/National Institute of Neurological Disorders and Stroke (NS073829 and NS089701 to H. Z. and NS072113 and NS084089 to X.G.X). The content is the author’s responsibility and does not necessarily represent the official view of the NIH institutes.

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The authors declare that no conflict of interest exists.

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Authors and Affiliations

  1. Department of Pathology, Thomas Jefferson University, JAH506, 1020 Locust Street, Philadelphia, PA, 19107, USA

    Qinxue Wu, Mujun Liu, Cao Huang, Bo Huang, Niansheng Li & Xu-Gang Xia

  2. Department of Neurology, Thomas Jefferson University, 1020 Locust Street, Philadelphia, PA, 19107, USA

    Xionghao Liu & Hongxia Zhou

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  1. Qinxue Wu
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  2. Mujun Liu
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  7. Hongxia Zhou
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  8. Xu-Gang Xia
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Correspondence to Hongxia Zhou or Xu-Gang Xia.

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H. Zhou and X. G. Xia are senior authors.

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Wu, Q., Liu, M., Huang, C. et al. Pathogenic Ubqln2 gains toxic properties to induce neuron death. Acta Neuropathol 129, 417–428 (2015). https://doi.org/10.1007/s00401-014-1367-y

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  • DOI: https://doi.org/10.1007/s00401-014-1367-y

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