Expression of ALS-linked TDP-43 mutant in astrocytes causes non-cell-autonomous motor neuron death in rats

Authors

  • Jianbin Tong,

    1. Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA
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    • These authors contributed equally to this work.
    • Present address: Department of Anesthesiology, The Third Xiang-Ya Hospital of Central South University, 138 Tong-Zi-Po Road, Changsha, 410013 Hunan, China.
  • Cao Huang,

    1. Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA
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    • These authors contributed equally to this work.
  • Fangfang Bi,

    1. Department of Neurology, Thomas Jefferson University, Philadelphia, PA, USA
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  • Qinxue Wu,

    1. Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA
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  • Bo Huang,

    1. Department of Neurology, Thomas Jefferson University, Philadelphia, PA, USA
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  • Xionghao Liu,

    1. Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA
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  • Fang Li,

    1. Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA
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  • Hongxia Zhou,

    Corresponding author
    1. Department of Neurology, Thomas Jefferson University, Philadelphia, PA, USA
    • Corresponding authors. Department of Neurology, Thomas Jefferson University, 1020 Locust Street, Philadelphia, PA 19107, USA. Tel.:+1 215 503 5916; Fax:+1 215 923 3801; E-mail: Hongxia.zhou@jefferson.eduDepartment of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, JAH506, 1020 Locust Street, Philadelphia, PA 19107, USA. Tel.:+1 215 503 9156; Fax:+1 215 923 3808; E-mail: Xugang.xia@jefferson.edu

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  • Xu-Gang Xia

    Corresponding author
    1. Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA
    • Corresponding authors. Department of Neurology, Thomas Jefferson University, 1020 Locust Street, Philadelphia, PA 19107, USA. Tel.:+1 215 503 5916; Fax:+1 215 923 3801; E-mail: Hongxia.zhou@jefferson.eduDepartment of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, JAH506, 1020 Locust Street, Philadelphia, PA 19107, USA. Tel.:+1 215 503 9156; Fax:+1 215 923 3808; E-mail: Xugang.xia@jefferson.edu

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Abstract

Mutation of Tar DNA-binding protein 43 (TDP-43) is linked to amyotrophic lateral sclerosis. Although astrocytes have important roles in neuron function and survival, their potential contribution to TDP-43 pathogenesis is unclear. Here, we created novel lines of transgenic rats that express a mutant form of human TDP-43 (M337V substitution) restricted to astrocytes. Selective expression of mutant TDP-43 in astrocytes caused a progressive loss of motor neurons and the denervation atrophy of skeletal muscles, resulting in progressive paralysis. The spinal cord of transgenic rats also exhibited a progressive depletion of the astroglial glutamate transporters GLT-1 and GLAST. Astrocytic expression of mutant TDP-43 led to activation of astrocytes and microglia, with an induction of the neurotoxic factor Lcn2 in reactive astrocytes that was independent of TDP-43 expression. These results indicate that mutant TDP-43 in astrocytes is sufficient to cause non-cell-autonomous death of motor neurons. This motor neuron death likely involves deficiency in neuroprotective genes and induction of neurotoxic genes in astrocytes.

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