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

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 mRNA s. Here we tested the effects of lentiviral Parkin and TDP‐43 expression on amino acid metabolism in the rat motor cortex using high frequency 13 C 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. image 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.