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.
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.