Top

Published in:

01-06-2009

PPAR-γ Agonist Azelaoyl PAF Increases Frataxin Protein and mRNA Expression. New Implications for the Friedreich’s Ataxia Therapy

Authors: Daniele Marmolino, Fabio Acquaviva, Michele Pinelli, Antonella Monticelli, Imma Castaldo, Alessandro Filla, Sergio Cocozza

Published in: The Cerebellum | Issue 2/2009

Abstract

Friedreich’s ataxia is a neurodegenerative disease due to frataxin deficiency, and thus, drugs increasing the frataxin amount are excellent candidates for therapy. By screening Gene Expression Omnibus profiles, we identified records showing a frataxin response to the peroxisome proliferator-activated receptors gamma (PPAR-γ) agonist rosiglitazone. We decided to investigate the effect of the PPAR-γ agonist Azelaoyl PAF on the frataxin protein and mRNA expression profile. We treated human neuroblastoma cells SKNBE and primary fibroblasts from skin biopsies from Friedreich’s ataxia (FRDA) patients and healthy controls with the PPAR-γ agonist Azelaoyl PAF. We show in this paper for the first time that Azelaoyl PAF significantly increases the intracellular frataxin levels by twofold in the neuroblastoma cell line SKNBE and fibroblasts from FRDA patients and that Azelaoyl PAF increases frataxin protein through a transcriptional mechanism. PPAR-γ agonist Azelaoyl PAF increases both messenger RNA and protein levels of frataxin. We hypothesize that PPAR-γ agonists could play a role in the treatment of FRDA, and our results offer the logical bases to further investigate the usefulness of this group of agents for the treatment of the FRDA.

Campuzano V, Montermini L, Lutz Y, Cova L, Hindelang C, Jiralerspong S, Trottier Y, Kish SJ, Faucheux B, Trouillas P, Authier FJ, Dürr A, Mandel JL, Vescovi A, Pandolfo M, Koenig M (1997) Frataxin is reduced in Friedreich ataxia patients and is associated with mitochondrial membranes. Hum Mol Genet 6:1771–1780PubMedCrossRef

Pianese L, Turano M, Lo Casale MS, De Biase I, Giacchetti M, Monticelli A, Criscuolo C, Filla A, Cocozza S (2004) Real time PCR quantification of frataxin mRNA in the peripheral blood leucocytes of Friedreich ataxia patients and carriers. J Neurol Neurosurg Psychiatry 75:1061–1063PubMedCrossRef

Wells RD (2008) DNA triplexes and Friedreich ataxia. FASEB J 22:1625–1634PubMedCrossRef

Herman D, Jenssen K, Burnett R, Soragni E, Perlman SL, Gottesfeld JM (2006) Histone deacetylase inhibitors reverse gene silencing in Friedreich’s ataxia. Nat Chem Biol 2:551–558PubMedCrossRef

Greene E, Mahishi L, Entezam A, Kumari D, Usdin K (2007) Repeat-induced epigenetic changes in intron 1 of the frataxin gene and its consequences in Friedreich ataxia. Nucleic Acids Res 35:3383–3390PubMedCrossRef

Castaldo I, Pinelli M, Monticelli A, Acquaviva F, Giacchetti M, Filla A, Sacchetti S, Keller S, Avvedimento VE, Chiariotti L, Cocozza S (2008) DNA methylation in intron 1 of the frataxin gene is related to GAA repeat length and age of onset in Friedreich’s ataxia patients. J Med Gen 45(12):808–812.CrossRef

Babcock M, de Silva D, Oaks R, Davis-Kaplan S, Jiralerspong S, Montermini L, Pandolfo M, Kaplan J (1997) Regulation of mitochondrial iron accumulation by Yfh1p, a putative homolog of frataxin. Science 276:1709–1712PubMedCrossRef

Gakh O, Park S, Liu G, Macomber L, Imlay JA, Ferreira GC, Isaya G (2006) Mitochondrial iron detoxification is a primary function of frataxin that limits oxidative damage and preserves cell longevity. Hum Mol Genet 15:467–479PubMedCrossRef

Wilson RB (2006) Iron dysregulation in Friedreich ataxia. Semin Pediatr Neurol 13:166–175PubMedCrossRef

10.

Blanquart C, Barbier O, Fruchart JC, Staels B, Glineur C (2003) Peroxisome proliferator-activated receptors: regulation of transcriptional activities and roles in inflammation. J Steroid Biochem Mol Biol 85:267–273PubMedCrossRef

11.

Wu Z, Puigserver P, Andersson U, Zhang C, Adelmant G, Mootha V, Troy A, Cinti S, Lowell B, Scarpulla RC, Spiegelman BM (1999) Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1. Cell 98:115–124PubMedCrossRef

12.

Kelly DP, Scarpulla RC (2004) Transcriptional regulatory circuits controlling mitochondrial biogenesis and function. Genes Dev 18:357–368PubMedCrossRef

13.

Richter B, Bandeira-Echtler E, Bergerhoff K, Clar C, Ebrahim SH (2007) Rosiglitazone for type 2 diabetes mellitus. Cochrane Database Syst Rev 18(3):CD006063

14.

Heneka MT, Landreth GE (2007) PPARs in the brain. Biochim Biophys Acta 1771:1031–1045PubMed

15.

Torchia J, Rose DW, Inostroza J, Kamei Y, Westin S, Glass CK, Rosenfeld MG (1997) The transcriptional co-activator p/CIP binds CBP and mediates nuclear-receptor function. Nature 387:677–684PubMedCrossRef

16.

Acquaviva F, Castaldo I, Filla A, Giacchetti M, Marmolino D, Monticelli A, Pinelli M, Saccà F, Cocozza S (2008) Recombinant human erythropoietin increases frataxin protein expression without increasing mRNA Expression. Cerebellum 7(3):360–365PubMedCrossRef

17.

Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 25:402–408PubMedCrossRef

18.

Keen HL, Ryan MJ, Beyer A, Mathur S et al (2004) Gene expression profiling of potential PPARgamma target genes in mouse aorta. Physiol Genomics 18(1):33–42PubMedCrossRef

19.

Girnun GD, Naseri E, Vafai SB, Qu L, Szwaya JD, Bronson R, Alberta JA, Spiegelman BM (2007) Synergy between PPARgamma ligands and platinum-based drugs in cancer. Cancer Cell 11:395–406PubMedCrossRef

20.

Pandolfo M (2002) Frataxin deficiency and mitochondrial dysfunction. Mitochondrion 2:87–93PubMedCrossRef

21.

Pandolfo M (2008) Drug Insight: antioxidant therapy in inherited ataxias. Nat Clin Pract Neurol 4:86–96PubMedCrossRef

22.

Lim F, Palomo GM, Mauritz C, Giménez-Cassina A, Illana B, Wandosell F, Díaz-Nido J (2007) Functional recovery in a Friedreich’s ataxia mouse model by frataxin gene transfer using an HSV-1 amplicon vector. Mol Ther 15(6):1072–1078PubMed

23.

Runko AP, Griswold AJ, Min KT (2008) Overexpression of frataxin in the mitochondria increases resistance to oxidative stress and extends lifespan in Drosophila. FEBS Lett 582:715–719PubMedCrossRef

24.

Turano M, Tammaro A, De Biase I, Lo Casale MS, Ruggiero G, Monticelli A, Cocozza S, Pianese L (2003) 3-Nitropropionic acid increases frataxin expression in human lymphoblasts and in transgenic rat PC12 cells. Neurosci Lett 350:184–186PubMedCrossRef

25.

Sarsero JP, Li L, Wardan H, Sitte K, Williamson R, Ioannou PA (2003) Upregulation of expression from the FRDA genomic locus for the therapy of Friedreich ataxia. J Gene Med 5:72–81PubMedCrossRef

26.

Rai M, Soragni E, Jenssen K, Burnett R, Herman D, Coppola G, Geschwind DH, Gottesfeld JM, Pandolfo M (2008) HDAC inhibitors correct frataxin deficiency in a Friedreich ataxia mouse model. PLoS One 3:e1958PubMedCrossRef

27.

Sturm B, Stupphann D, Kaun C, Boesch S, Schranzhofer M, Wojta J, Goldenberg H, Scheiber-Mojdehkar B (2005) Recombinant human erythropoietin: effects on frataxin expression in vitro. Eur J Clin Invest 35:711–717PubMedCrossRef

28.

Ahmed W, Ziouzenkova O, Brown J, Devchand P, Francis S, Kadakia M, Kanda T, Orasanu G, Sharlach M, Zandbergen F, Plutzky J (2007) PPARs and their metabolic modulation: new mechanisms for transcriptional regulation? J Intern Med 262:184–198PubMedCrossRef

29.

Lee KJ, Jang YH, Lee H, Yoo HS, Lee SR (2008) PPARgamma agonist pioglitazone reduces [corrected] neuronal cell damage after transient global cerebral ischemia through matrix metalloproteinase inhibition. Eur J Neurosci 27:334–342PubMedCrossRef

Title: PPAR-γ Agonist Azelaoyl PAF Increases Frataxin Protein and mRNA Expression. New Implications for the Friedreich’s Ataxia Therapy
Authors: Daniele Marmolino
Fabio Acquaviva
Michele Pinelli
Antonella Monticelli
Imma Castaldo
Alessandro Filla
Sergio Cocozza
Publication date: 01-06-2009
Publisher: Springer-Verlag
Published in: The Cerebellum / Issue 2/2009
Print ISSN: 1473-4222
Electronic ISSN: 1473-4230
DOI: https://doi.org/10.1007/s12311-008-0087-z

At a glance: The STEP trials

Springer Medicine

PPAR-γ Agonist Azelaoyl PAF Increases Frataxin Protein and mRNA Expression. New Implications for the Friedreich’s Ataxia Therapy

Abstract

At a glance: The STEP trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 2/2009

Spinocerebellar Ataxia Type 23: A Genetic Update

Animal Models to Study Thyroid Hormone Action in Cerebellum

Altered Heart Rate Control in Response to Postural Change in Patients with Machado–Joseph Disease (SCA3)

PTPRR, Cerebellum, and Motor Coordination

Interhemispheric Transfer of Predictive Force Control During Grasping in Cerebellar Disorders

Iron, Copper, and Zinc Distribution of the Cerebellum