Parkin reverses TDP-43-induced cell death and failure of amino acid homeostasis

Authors

  • Michaeline Hebron,

    1. Department of Neuroscience, Georgetown University Medical Center, Washington, District of Columbia, USA
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  • Wenqiang Chen,

    1. Department of Neuroscience, Georgetown University Medical Center, Washington, District of Columbia, USA
    2. Department of Traditional Chinese Medicine, Xuanwu Hospital, Capital Medical University, Beijing, China
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  • Matthew J. Miessau,

    1. Drug Discovery Program, Lombardi Cancer Center, Georgetown University Medical Center, Washington, District of Columbia, USA
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  • Irina Lonskaya,

    1. Department of Neuroscience, Georgetown University Medical Center, Washington, District of Columbia, USA
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  • Charbel E.-H. Moussa

    Corresponding author
    1. Department of Neuroscience, Georgetown University Medical Center, Washington, District of Columbia, USA
    • Address correspondence and reprint requests to Charbel E.-H. Moussa, Laboratory for Dementia and Parkinsonism, Department of Neuroscience, Georgetown University School of Medicine, 3970 Reservoir Rd, NW, TRB, Room WP09B, Washington DC 20057, USA. E-mail: cem46@georgetown.edu

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Abstract

The E3 ubiquitin ligase Parkin plays a central role in the pathogenesis of many neurodegenerative diseases. Parkin promotes specific ubiquitination and affects the localization of transactivation response DNA-binding protein 43 (TDP-43), which controls the translation of thousands of mRNAs. Here we tested the effects of lentiviral Parkin and TDP-43 expression on amino acid metabolism in the rat motor cortex using high frequency 13C NMR spectroscopy. TDP-43 expression increased glutamate levels, decreased the levels of other amino acids, including glutamine, aspartate, leucine and isoleucine, and impaired mitochondrial tricarboxylic acid cycle. TDP-43 induced lactate accumulation and altered the balance between excitatory (glutamate) and inhibitory (GABA) neurotransmitters. Parkin restored amino acid levels, neurotransmitter balance and tricarboxylic acid cycle metabolism, rescuing neurons from TDP-43-induced apoptotic death. Furthermore, TDP-43 expression led to an increase in 4E-BP levels, perhaps altering translational control and deregulating amino acid synthesis; while Parkin reversed the effects of TDP-43 on the 4E-BP signaling pathway. Taken together, these data suggest that Parkin may affect TDP-43 localization and mitigate its effects on 4E-BP signaling and loss of amino acid homeostasis.

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TDP-43 increases 4E-BP levels and alters translational control, leading to elevation in glutamate (Glu) and lactate (Lac) and attenuation of glutamine (Gln), aspartate (Asp), leucine (Leu), and isoleucine (IsoLeu). TDP-43 decreases GABA levels and inhibits mitochondrial tri-carboxylic acid cycle (TCA), leading to neuronal loss. Parkin facilitates nuclear TDP-43 translocation to the cytoplasm and decreases oxidative stress, protects TCA cycle and promotes cell survival.

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