Journal article
Frataxin silencing inactivates mitochondrial Complex I in NSC34 motoneuronal cells and alters glutathione homeostasis
International journal of molecular sciences, v 15(4), pp 5789-5806
04 Apr 2014
PMID: 24714088
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Friedreich's ataxia (FRDA) is a hereditary neurodegenerative disease characterized by a reduced synthesis of the mitochondrial iron chaperon protein frataxin as a result of a large GAA triplet-repeat expansion within the first intron of the frataxin gene. Despite neurodegeneration being the prominent feature of this pathology involving both the central and the peripheral nervous system, information on the impact of frataxin deficiency in neurons is scant. Here, we describe a neuronal model displaying some major biochemical and morphological features of FRDA. By silencing the mouse NSC34 motor neurons for the frataxin gene with shRNA lentiviral vectors, we generated two cell lines with 40% and 70% residual amounts of frataxin, respectively. Frataxin-deficient cells showed a specific inhibition of mitochondrial Complex I (CI) activity already at 70% residual frataxin levels, whereas the glutathione imbalance progressively increased after silencing. These biochemical defects were associated with the inhibition of cell proliferation and morphological changes at the axonal compartment, both depending on the frataxin amount. Interestingly, at 70% residual frataxin levels, the in vivo treatment with the reduced glutathione revealed a partial rescue of cell proliferation. Thus, NSC34 frataxin silenced cells could be a suitable model to study the effect of frataxin deficiency in neurons and highlight glutathione as a potential beneficial therapeutic target for FRDA.
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Details
- Title
- Frataxin silencing inactivates mitochondrial Complex I in NSC34 motoneuronal cells and alters glutathione homeostasis
- Creators
- Barbara Carletti - Unit for Neuromuscular and Neurodegenerative Diseases, Children's Hospital and Research Institute "Bambino Gesù", Piazza S. Onofrio 4, 00165 Rome, Italy. carletti.barbara@tiscali.itEmanuela Piermarini - Bambino Gesù Children's HospitalGiulia Tozzi - Bambino Gesù Children's HospitalLorena Travaglini - Bambino Gesù Children's HospitalAlessandra Torraco - Bambino Gesù Children's HospitalAnna Pastore - Bambino Gesù Children's HospitalMarco Sparaco - Azienda Ospedaliera G.RummoSara Petrillo - Bambino Gesù Children's HospitalRosalba Carrozzo - Bambino Gesù Children's HospitalEnrico Bertini - Bambino Gesù Children's HospitalFiorella Piemonte - Bambino Gesù Children's Hospital
- Publication Details
- International journal of molecular sciences, v 15(4), pp 5789-5806
- Publisher
- MDPI
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Neurobiology and Anatomy
- Web of Science ID
- WOS:000336841200040
- Scopus ID
- 2-s2.0-84898758220
- Other Identifier
- 991021900207504721
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InCites Highlights
Data related to this publication, from InCites Benchmarking & Analytics tool:
- Web of Science research areas
- Biochemistry & Molecular Biology
- Chemistry, Multidisciplinary