FOXRED1 silencing in mice: a possible animal model for Leigh syndrome
- 209 Downloads
Leigh syndrome (LS) is one of the most puzzling mitochondrial disorders, which is also known as subacute necrotizing encephalopathy. It has an incidence of 1 in 77,000 live births worldwide with poor prognosis. Currently, there is a poor understanding of the underlying pathophysiological mechanisms of the disease without any available effective treatment. Hence, the inevitability for developing suitable animal and cellular models needed for the development of successful new therapeutic modalities. In this short report, we blocked FOXRED1 gene with small interfering RNA (siRNA) using C57bl/6 mice. Results showed neurobehavioral changes in the injected mice along with parallel degeneration in corpus striatum and sparing of the substantia nigra similar to what happen in Leigh syndrome cases. FOXRED1 blockage could serve as a new animal model for Leigh syndrome due to defective CI, which echoes damage to corpus striatum and affection of the central dopaminergic system in this disease. Further preclinical studies are required to validate this model.
KeywordsFOXRED1 Neurodegenerative diseases Leigh syndrome Gene silencing
This work was supported by a grant from the Egyptian Science and Technology Development Fund (STDF) through Basic and Applied Research Grants (BARG) program, grant number (13892) [MS].
- Blandini F, Cova L, Armentero M, Zennaro E, Levandis G, Bossolasco P, Calzarossa C, Mellone M, Giuseppe B, Deliliers G, Polli E, Nappi G, Silani V (2010) Transplantation of undifferentiated human mesenchymal stem cells protects against 6-hydroxy dopamine neurotoxicity in the rat. Cell Transplant 19(2):203–217PubMedCrossRefGoogle Scholar
- Calvo SE, Tucker EJ, Compton AG, Kirby DM, Crawford G, Burtt NP, Rivas M, Guiducci C, Bruno DL, Goldberger OA, Redman MC, Wiltshire E, Wilson CJ, Altshuler D, Gabriel SB, Daly MJ, Thorburn DR, Mootha VK (2010) High-throughput, pooled sequencing identifies mutations in NUBPL and FOXRED1 in human complex I deficiency. Nat Genet 42(10):851–858PubMedPubMedCentralCrossRefGoogle Scholar
- DiMauro S, Schon EA, Carelli V, Hirano M (2013) The clinical maze of mitochondrial neurology. Nat Rev Neurol 9(8):429–444Google Scholar
- Franklin KBJ, PG (1997) The mouse brain in stereotaxic coordinates, 2nd edn. Academic Press, San Diego, CAGoogle Scholar
- Lazarou M, Thorburn DR, Ryan MT, McKenzie M (2009) Assembly of mitochondrial complex I and defects in disease. Biochimica et Biophysica Acta (BBA)-Molecular. Cell Res 1793(1):78–88Google Scholar
- Lebre AS, Rio M, Faivre d'Arcier L, Vernerey D, Landrieu P, Slama A, Jardel C, Laforet P, Rodriguez D, Dorison N, Galanaud D, Chabrol B, Paquis-Flucklinger V, Grevent D, Edvardson S, Steffann J, Funalot B, Villeneuve N, Valayannopoulos V, de Lonlay P, Desguerre I, Brunelle F, Bonnefont JP, Rotig A, Munnich A, Boddaert N (2011) A common pattern of brain MRI imaging in mitochondrial diseases with complex I deficiency. J Med Genet 48(1):16–23PubMedCrossRefGoogle Scholar
- Pagliarini DJ, Calvo SE, Chang B, Sheth SA, Vafai SB, Ong SE, Walford GA, Sugiana C, Boneh A, Chen WK, Hill DE, Vidal M, Evans JG, Thorburn DR, Carr SA, Mootha VK (2008) A mitochondrial protein compendium elucidates complex I disease biology. Cell 134(1):112–123PubMedPubMedCentralCrossRefGoogle Scholar
- Zurita Rendón O, Antonicka H, Horvath R, Shoubridge EA (2016) A mutation in the Flavin adenine dinucleotide-dependent oxidoreductase FOXRED1 results in cell-type-specific assembly defects in oxidative phosphorylation complexes I and II. Mol Cell Biol 36(16):2132–2140PubMedPubMedCentralCrossRefGoogle Scholar