Brain mitochondrial proteome alteration driven by creatine deficiency suggests novel therapeutic venues for creatine deficiency syndromes

Giusti, L.; Molinaro, A.; Alessandrì, M. G.; Boldrini, C.; Ciregia, Federica; Lacerenza, S.; Ronci, M.; Urbani, A.; Cioni, G.; Mazzoni, M. R.; Pizzorusso, T.; Lucacchini, A.; Baroncelli, L.

doi:10.1016/j.neuroscience.2019.03.030

Article (Scientific journals)

Brain mitochondrial proteome alteration driven by creatine deficiency suggests novel therapeutic venues for creatine deficiency syndromes

Giusti, L.; Molinaro, A.; Alessandrì, M. G. et al.

2019 • In Neuroscience

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https://hdl.handle.net/2268/261157

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10.1016/j.neuroscience.2019.03.030

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31029731

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Abstract :

[en] 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. © 2019 Elsevier Ltd

Disciplines :

Neurology

Author, co-author :

Giusti, L.; Department of Clinical and Experimental Medicine, University of Pisa, Pisa, I-56126, Italy, School of Pharmacy, University of Camerino, Camerino, I-62032, Italy

Molinaro, A.; Department of Neuroscience, Psychology, Drug Research and Child Health NEUROFARBA, University of Florence, Florence, I-50135, Italy, Institute of Neuroscience, National Research Council (CNR), Pisa, I-56124, Italy

Alessandrì, M. G.; Department of Developmental Neuroscience, IRCCS Stella Maris Foundation, Pisa, I-56128, Italy

Boldrini, C.; Department of Pharmacy, University of Pisa, Pisa, I-56126, Italy

Ciregia, Federica ; Université de Liège - ULiège > I3-Rheumatology

Lacerenza, S.; Department of Pharmacy, University of Pisa, Pisa, I-56126, Italy

Ronci, M.; Department of Medical, Oral and Biotechnological Sciences, University G. d'Annunzio of Chieti-Pescara, Chieti, I-66100, Italy

Urbani, A.; Institute of Biochemistry and Clinical Chemistry, Catholic university of the sacred heart, Rome, I-00168, Italy

Cioni, G.; Department of Clinical and Experimental Medicine, University of Pisa, Pisa, I-56126, Italy, Department of Developmental Neuroscience, IRCCS Stella Maris Foundation, Pisa, I-56128, Italy

Mazzoni, M. R.; Department of Pharmacy, University of Pisa, Pisa, I-56126, Italy

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Language :

English

Title :

Brain mitochondrial proteome alteration driven by creatine deficiency suggests novel therapeutic venues for creatine deficiency syndromes

Publication date :

2019

Journal title :

Neuroscience

ISSN :

0306-4522

eISSN :

1873-7544

Publisher :

Elsevier Ltd

Peer reviewed :

Peer Reviewed verified by ORBi

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