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 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.
['Hebron|Michaeline|M|', 'Chen|Wenqiang|W|', 'Miessau|Matthew J|MJ|', 'Lonskaya|Irina|I|', 'Moussa|Charbel E-H|CE|']
D000596:Amino Acids D000818:Animals D015153:Blotting, Western D002352:Carrier Proteins D053148:Caspase 3 D016923:Cell Death D002952:Citric Acid Cycle D005470:Fluorometry D005822:Genetic Vectors D006706:Homeostasis D047908:Intracellular Signaling Peptides and Proteins D016086:Lentivirus D009682:Magnetic Resonance Spectroscopy D008297:Male D009044:Motor Cortex D018377:Neurotransmitter Agents D010750:Phosphoproteins D051381:Rats D017207:Rats, Sprague-Dawley D057177:TDP-43 Proteinopathies D058570:TOR Serine-Threonine Kinases D044767:Ubiquitin-Protein Ligases D005680:gamma-Aminobutyric Acid
Parkin amino acids TDP-43 13C NMR ALS