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Quinone for RC deficiency treatment - PowerPoint PPT Presentation

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Quinone for RC deficiency treatment

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  1. Quinone for RC deficiency treatment

  2. O C C C C C CH CH CH CH CH CH CH CH CH CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH3 CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH2 C C C C C C C C C C O CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 Ubiquinone = Coenzyme Q = CoQ10 intermembrane space c inner membrane CIII UQ C I CV UQ Ubiquinone function in mitochondrial respiratory chain CIV CII matrix NADH O2 H2O Succinate ATP ADP

  3. CH CH2 CH2 C n CH3 O O O P O O O- P OH C O- O- H H C C C C H H C O OH C C C C C CH CH CH CH CH CH CH CH CH CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH3 CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH2 C C C C C C C C C C O CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 Quinone biosynthesis pathway mevalonate dimethylallyl-PP isopentenyl-PP tyrosine geranyl-PP 4-OH-phenylpyruvate transtransfarnesyl-PP prephenate geranylgeranyl-PP chorismate 4-OH-benzoate polyprenyl-PP polyprenyl-OH-benzoate Ubiquinone

  4. CH CH2 CH2 C 6 CH3 O O O P O O O- P OH C O- O- H H C C C C H H C OH Quinone biosynthesis pathway mevalonate dimethylallyl-PP isopentenyl-PP S. cerevisiae tyrosine geranyl-PP 4-OH-phenylpyruvate transtransfarnesyl-PP prephenate geranylgeranyl-PP chorismate COQ1 4-OH-benzoate hexaprenyl-PP COQ2 hexaprenyl-OH-benzoate COQ4 COQ8 COQ9 COQ10 COQ3 COQ6 COQ5 COQ7 Ubiquinone CoQ6

  5. CH CH2 CH2 C 10 CH3 O O O P O O O- P OH C O- O- H H C C C C H H C OH mevalonate Quinone biosynthesis pathway dimethylallyl-PP isopentenyl-PP H. sapiens tyrosine geranyl-PP 4-OH-phenylpyruvate transtransfarnesyl-PP prephenate FPP geranylgeranyl-PP chorismate PDSS1+PDSS2 4-OH-benzoate decaprenyl-PP COQ2 decaprenyl-OH-benzoate COQ4 COQ3 COQ8 COQ9 COQ10 ADCK1 ADCK2 ADCK4 ADCK5 COQ6 COQ5 COQ7 Ubiquinone CoQ10

  6. Deafness Mental retardation Obesity D308E D308E mevalonate Deafness Nephrotic syndrome Mental retardation Myopathy Ataxia Cataract… dimethylallyl-PP isopentenyl-PP geranyl-PP transtransfarnesyl-PP tyrosine geranylgeranyl-PP S382L S382L N401fsX415 N401fsX415 decaprenyl-PP 4-OH-benzoate Neurological distress Liver failure Nephrotic syndrome decaprenyl-OH-benzoate Ataxia Seizures Mild mental retardation CoQ10 R213W G272V E551K E551K G272D c.[1812-1813insG] Genes for ubiquinone deficiencies PDSS1 PDSS2 COQ2 COQ8/CABC1

  7. Treatment of ubiquinone deficiency Patient with PDSS2 mutation Before treatment  Wheel-chair bound Neck muscle weakness Could not grasp Reduced visual contact Drooling, cataract Needed a nap in afternoon After 14 mths of treatment: Can stand and walk unaided Head control Can take, hold and give back Fixes and smiles Diseappeared Does not want to go to bed at night

  8. O CH3 C CH3O C C C C CH CH2 H C CH3O CH2 C x 10 O CH3 oral idebenone treatment (10 mg/kg/day)  failed to improve his condition and worsened the course of the disease O CH3 C CH3O C Idebenone C C CH2 CH2 CH2 CH2 CH2OH C CH2 CH2 CH2 CH2 CH2 CH3O C O Treatment of ubiquinone deficiency Patient with COQ8 mutation P1: cerebellar ataxia seizures trunk hypotonia oral CoQ10 treatment (5-10 mg/kg/day)  no clinical benefits Coenzyme Q10 Ubiquinone

  9. Treatment of ubiquinone deficiency Patients:  clinical improvement in some cases Patients mitochondria:  rapid activation of CII+III activity by exogenous quinone Yeast coq mutants:  rescue of growth by quinone supplementation The respiratory chain deficiency is rapidly corrected by exogenous quinone Insufficient uptake of CoQ10 across the blood-brain barrier in patients

  10. Friedreich ataxia • Progressive cerebellar ataxia • Lack of deep tendon reflexesHypertrophic cardiomyopathy • Diabetes mellitus (10%) • Carbohydrate intolerance (20%) • Autosomal recessive • Frequence: 1/50,000 • Gene localisation: 9q13-q21 • (Chamberlain et al, Nature 1988) • The gene encodes a 210 AA protein, frataxin • (Campuzano et al, Science 1996) • GAA repeat expansion in the first intron

  11. Ssq1 Jac1 Mge1 S S S S Grx5 Yfh1 Yah1 Arh1 Isa1/2 Nfu1 Iron-sulfur synthesis in yeast CIA machinery Cdf1, Nbp5, Nar1 Yeast Yfh1 = Human frataxin extramitochondrial Fe-S protein cytosol mitochondria mitochondrial Fe-S protein S S Ala NADH Isu1/2 Nfs1 Cys Mrs3/4  from R. Lill Fe2+

  12. Iron-sulfur proteins targeted in Friedreich ataxia ISp Aconitase Cytosol Outer membrane c UQ C I CIII Inner membrane ISp ISp CIV CII ISp Matrix NADH O2 Succinate Krebs cycle ISp : iron-sulfur protein ISp Aconitase

  13. Triplet expansion Fe2+ Frataxin ISPs O2 Respiratory chain deficiency

  14. Chelators Fe2+ Frataxin ISPs O2 Antioxidants ?

  15. C19H29O5 MW: 338 O CH3 C CH3O C C CH2 CH2 CH2 CH2 CH2OH CH2 CH2 CH2 CH2 CH2 CH3O C O C C Idebenone 6-(10-hydroxydecyl)-2,3-dimethoxy- 5-methyl-1,4-benzoquinone Quinone ring Side chain

  16. The effect of idebenone oral supplementation (6 months) on the left-ventricular mass index in 52 FRDA patients Increased >20% 15% Stable or decreased <20% 39% 46% Decreased >-20% 85%

  17. What about the neurological condition in FRDA patients treated by idebenone ? • Patients, families and/or clinicians often report: • - Decreased fatigability • - Improvement of delicate movements (handwriting,drawing, • control of the wheelchair commands) • - Better voice (use of the phone) • - Decreased swallowing difficulties • Yet ataxia and deep tendon reflexes did not change significantly • after 1 year treatment

  18. TRIALING IDEBENONE IN FRDA 3 patients / 6 m treat. / decreased cardiac hypertrophy / no improvement of ataxia (1998 Hôpital Necker, Paris, France; The Lancet) 8 patients / 1 y treat. / scores of ARS scale improved in all patients (2001 Hospital Sant Joan de Déu, Barcelona, Spain; Arthur et al. Euromit 5) 9 patients (5 treated) / 6 weeks treat. / neither improvement of cardiac hypertrophy nor of neurological condition (2001 St Josef Hospital, Bochum, Germany; Schöls et al. Neurosc. Lett) 11 patients / 1 y treat. / decreased heart hypertrophy in all patients / no improvement of ataxia (2001 Hôpital Sainte-Justine, Montréal, Canada; Emond et al, WebSite) 29 patients (15 treated) / 6 m treat. / reduced heart hypertrophy / no improvement of the ARS scale (2001 Milano, Italy; for ataxia (Mariotti et al. J Neurol.) 38 patients / 6 m treat. / decreased cardiac hypertrophy (50% of the patients) / no improvement of ataxia (2002 Hôpital Necker, Paris, France; Heart; Free Rad. Res.) 50 patients / 1 y treat. / decreased cardiac hypertrophy / no improvement of ataxia (2002 The French official trial; Hôpital de la Salpetrière et Hôpital Necker, Paris, France)

  19. Quinone for RC deficiency treatment Restoring electron flow  replacement therapy in ubiquinone biosynthesis defects ubiquinone (CoQ10) Increasing antioxidant defenses  evidence of mitochondrial oxidative stress  ubiquinone biosynthesis defects idebenone