Brain mitochondrial proteome alteration driven by creatine deficiency suggests novel therapeutic venues for creatine deficiency syndromes. (15th June 2019)

• Record Type: Journal Article
• Authors: Giusti, Laura; Molinaro, Angelo; Alessandrì, Maria Grazia; Boldrini, Claudia; Ciregia, Federica; Lacerenza, Serena; Ronci, Maurizio; Urbani, Andrea; Cioni, Giovanni; Mazzoni, Maria Rosa; Pizzorusso, Tommaso; Lucacchini, Antonio; Baroncelli, Laura
• Is Part Of: Neuroscience. Volume 409(2019)
• Page Start: 276
• Page End: 289
• Publication Date: 2019-06-15
• Subjects: 2DE Two dimensional electrophoresis -- ADP Adenosine diphosphate -- AGAT Arginine glycine amidinotransferase -- APS Ammonium persulfate -- ASDs Autism spectrum disorders -- ATP Adenosine triphosphate -- BSA Bovine serum albumin -- BSTFA N, O-Bis(trimethylsilyl)trifluoroacetamide -- CHAPS 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate -- CID Collision-induced dissociation -- CK Cr kinase -- CNS Central nervous system -- Cr Creatine -- CrT Creatine transporter -- CTD Creatine transporter deficiency -- DDA Data dependent acquisition -- dNTP Deoxynucleotide -- DTT Iodoacetamide, dithiothreitol -- ECL Enhanced chemiluminescence -- EDTA Ethylenediaminetetraacetic acid -- EGLN Egl nine homolog 1 -- ESRRG Estrogen-related receptor gamma -- F Forward primer -- FDR False discovery rate -- FMR1 Fragile mental retardation protein 1 -- GAPDH Glyceraldehyde-3-phosphate dehydrogenase -- GC/MS Gas Chromatography/Mass Spectrometry -- GNAO Guanine nucleotide-binding protein G(o) subunit alpha -- HD UHR-TOF High-Definition Ultra High Resolution- Time of Flight -- HRP Horseradish peroxidase -- I.D. Internal Diameter -- I.S. Internal Standard -- IB Isolation buffer -- IPA Ingenuity Pathway Analysis -- IPG Immobilized pH gradient -- KDM5A Lysine-specific demethylase 5A -- L Length -- MAPK1/ERK2 Mitogen-activated protein kinase 1/ Extracellular signal–regulated kinase 2 -- MW Molecular weight -- mTOR Mammalian target of rapamycin -- nano-ESI Nano-electrospray ionization -- nano-LC–MS/MS Nanoscale liquid chromatography coupled to tandem mass spectrometry -- Nrf2 or NFE2L2 Nuclear factor erythroid 2–related factor 2 -- OD Optical density -- PCr phosphoCr -- PCR Polymerase Chain Reaction -- PDIA4 Protein disulfide-isomerase -- pI Isoelectric point -- PLK Pyridoxal kinase -- PP2AB Serine/threonine-protein phosphatase 2A catalytic subunit beta -- PPARGC1A Peroxisome proliferator-activated receptor gamma coactivator 1-alpha -- PPIA Peptidyl-prolyl-cis-trans isomerase A -- PRDX5 Peroxiredoxin 5 -- PRDX6 Peroxiredoxin 6 -- ps particle size -- PSM Peptide spectrum-match -- PSMG1 Proteasome assembly chaperone 1 -- R Reverse primer -- Rictor Rapamycin-insensitive companion of mTOR -- ROS Reactive oxygen species -- RuBP Ruthenium II tris (bathophenantroline disulfonate) tetrasodium salt -- SD Standard deviation -- SDS-PAGE Sodium Dodecyl Sulfate–PolyAcrylamide Gel Electrophoresis -- SDS Sodium dodecyl sulfate -- SEM Standard error of the mean -- SIM Single ion monitoring mode -- SOD1 Superoxide dismutase 1 -- TEMED Tetramethylethylenediamine -- TMCS Trimethylchlorosilane -- UQCRB Ubiquinol-cytochrome c reductase binding protein -- WB Western blot -- WT Wild-type; creatine -- creatine deficiency -- metabolism -- mitochondria -- proteomics -- oxidative stress; Neurochemistry -- Periodicals; Neurophysiology -- Periodicals; Neurology -- Periodicals; Neurochimie -- Périodiques; Neurophysiologie -- Périodiques; Neurochemistry; Neurophysiology; Electronic journals; Periodicals; Electronic journals; 612.8
• DOI: 10.1016/j.neuroscience.2019.03.030
• Languages: English
• ISSNs: 0306-4522

Abstract

Abstract: Creatine (Cr) is a small metabolite with a central role in energy metabolism and mitochondrial function. Creatine deficiency syndromes are inborn errors of Cr metabolism causing Cr depletion in all body tissues and particularly in the nervous system. Patient symptoms involve intellectual disability, language and behavioral disturbances, seizures and movement disorders suggesting that brain cells are particularly sensitive to Cr depletion. Cr deficiency was found to affect metabolic activity and structural abnormalities of mitochondrial organelles; however a detailed analysis of molecular mechanisms linking Cr deficit, energy metabolism alterations and brain dysfunction is still missing. Using a proteomic approach we evaluated the proteome changes of the brain mitochondrial fraction induced by the deletion of the Cr transporter (CrT) in developing mutant mice. We found a marked alteration of the mitochondrial proteomic landscape in the brain of CrT deficient mice, with the overexpression of many proteins involved in energy metabolism and response to oxidative stress. Moreover, our data suggest possible abnormalities of dendritic spines, synaptic function and plasticity, network excitability and neuroinflammatory response. Intriguingly, the alterations occurred in coincidence with the developmental onset of neurological symptoms. Thus, cerebral mitochondrial alterations could represent an early response to Cr deficiency that could be targeted for therapeutic intervention. Graphical abstract: Unlabelled Image Highlights: Creatine deficiency leads to early alteration of mitochondrial proteomic landscape. Proteins involved in the energy metabolism chain and antioxidant enzymes are upregulated in creatine deficient brain. Spine dynamics, inflammatory response and ERK/MAPK pathway are affected by creatine deficiency. Mitochondrial alterations could be targeted for therapeutic intervention.