title: Parkin reverses TDP-43-induced cell death and failure of amino acid homeostasis.
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.
authors.affiliation: Department of Neuroscience, Georgetown University Medical Center, Washington, District of Columbia, USA.
authors.forename: Michaeline
authors.initials: M
authors.lastname: Hebron
authors.forename: Wenqiang
authors.initials: W
authors.lastname: Chen
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Miessau
authors.forename: Irina
authors.initials: I
authors.lastname: Lonskaya
authors.forename: Charbel E-H
authors.initials: CE
authors.lastname: Moussa
mesh_terms: D000596:Amino Acids / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D002352:Carrier Proteins / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects*; D002952:Citric Acid Cycle / Q000187:drug effects; D005470:Fluorometry; D005822:Genetic Vectors; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins; D016086:Lentivirus / Q000235:genetics; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D009044:Motor Cortex / Q000187:drug effects / Q000378:metabolism; D018377:Neurotransmitter Agents / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D057177:TDP-43 Proteinopathies / Q000188:drug therapy* / Q000473:pathology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000494:pharmacology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D000596:Amino Acids; D002352:Carrier Proteins; C499526:Eif4ebp1 protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D018377:Neurotransmitter Agents; D010750:Phosphoproteins; D005680:gamma-Aminobutyric Acid; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases; D053148:Caspase 3
keywords: 13C NMR; ALS; Parkin; TDP-43; amino acids