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Coenzyme Q10, Hyperhomocysteinemia and MTHFR C677T Polymorphism in Levodopa-treated Parkinson’s Disease Patients

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Abstract

There is evidence that increased homocysteine (Hcy) levels might accelerate dopaminergic cell death in Parkinson’s disease (PD) through neurotoxic effects. Homocysteine neurotoxicity mainly relies on redox state alterations. The present work was aimed at investigating the relationships between plasma Hcy concentrations and percent content of oxidized versus total Coenzyme Q10 (%CoQ10) in 60 PD patients and 82 healthy subjects. Both groups were screened for plasma levels of Hcy, vitamin B12, folate, %CoQ10 and C677T methylenetetrahydrofolate reductase (MTHFR) gene polymorphism. The MTHFR TT677 mutated genotype was found more frequently in patients than in controls (p = 0.01). In a multivariate analysis, Hcy levels and %CoQ10 were associated with the case/control category (p < 0.0001), MTHFR genotype (p < 0.0001) and their interaction term (p = 0.0015), even after adjusting for age, sex, folate and vitamin B12. Patients carrying the TT677 genotype exhibited the highest values of Hcy and %CoQ10 (p < 0.0001). Structural equation modelling evidenced that the TT677 genotype and levodopa daily dose were independently and directly correlated with Hcy (p < 0.0001, and p = 0.003, respectively), which, in turn, showed a significant correlation (p < 0.0001) with the %CoQ10 in PD patients. Our results suggest that increased Hcy levels act as mediator of the systemic oxidative stress occurring in PD, and %CoQ10 determination might be regarded as a predictor of toxic Hcy effects.

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References

  • Beal, M. F. (2003). Mitochondria, oxidative damage, and inflammation in Parkinson’s disease. Annals of the New York Academy of Science, 991, 120–131.

    Article  CAS  Google Scholar 

  • Caccamo, D., Condello, S., Gorgone, G., Crisafulli, G., Belcastro, V., Gennaro, S., et al. (2004). Screening for C677T and A1298C MTHFR polymorphisms in patients with epilepsy and risk of hyperhomocysteinemia. Neuromolecular Medicine, 6, 117–126.

    Article  PubMed  CAS  Google Scholar 

  • Caccamo, D., Gorgone, G., Currò, M., Parisi, G., Di Iorio, W., Menichetti, C., et al. (2007). Effect of MTHFR polymorphisms on hyperhomocysteinemia in levodopa-treated parkinsonian patients. Neuromolecular Medicine, 9, 249–254.

    Article  PubMed  CAS  Google Scholar 

  • Cartelli, D., Ronchi, C., Maggioni, M. G., Rodighiero, S., Giavini, E., & Cappelletti, G. (2010). Microtubule dysfunction precedes transport impairment and mitochondria damage in MPP+-induced neurodegeneration. Journal of Neurochemistry, 115(1), 247–258.

    Article  PubMed  CAS  Google Scholar 

  • Chango, A., Boisson, F., Barbe, F., Quilliot, D., Droesch, S., Pifster, M., et al. (2000). The effect of 677CT and 1298AC mutations on plasma homocysteine and 5,10-methylenetetrahydrofolate reductase activity in healthy subjects. British Journal of Nutrition, 83, 593–596.

    Article  PubMed  CAS  Google Scholar 

  • Chinta, S. J., & Andersen, J. K. (2006). Reversible inhibition of mitochondrial complex I activity following chronic dopaminergic glutathione depletion in vitro: implications for Parkinson’s disease. Free Radical Biology and Medicine, 41, 1442–1448.

    Article  PubMed  CAS  Google Scholar 

  • Condello, S., Currò, M., Ferlazzo, N., Caccamo, D., Satriano, J., & Ientile, R. (2011). Agmatine effects on mitochondrial membrane potential andNF-κB activation protect against rotenone-induced cell damage in human neuronal-like SH-SY5Y cells. Journal of Neurochemistry, 116(1), 67–75.

    Article  PubMed  CAS  Google Scholar 

  • Costa, C., Belcastro, V., Tozzi, A., Di Filippo, M., Tantucci, M., Siliquini, S., et al. (2008). Electrophysiology and pharmacology of striatal neuronal dysfunction induced by mitochondrial complex I inhibition. Journal of Neuroscience, 28, 8040–8052.

    Article  PubMed  CAS  Google Scholar 

  • de Lau, L. M., Koudstaal, P. J., van Meurs, J. B., Uitterlinden, A. G., Hofman, A., & Breteler, M. M. (2005). Methylenetetrahydrofolate reductase C677T genotype and PD. Annals of Neurology, 57(6), 927–930.

    Article  PubMed  Google Scholar 

  • Duan, W., Ladenheim, B., Cutler, R. G., Kruman, I. I., Cadet, J. L., & Mattson, M. P. (2002). Dietary folate deficiency and elevated homocysteine levels endanger dopaminergic neurons in models of Parkinson’s disease. Journal of Neurochemistry, 80, 101–110.

    Article  PubMed  CAS  Google Scholar 

  • Fasano, M., Bergamasco, B., & Lopiano, L. (2006). Modifications of the iron-neuromelanin system in Parkinson’s disease. Journal of Neurochemistry, 96, 909–916.

    Article  PubMed  CAS  Google Scholar 

  • Galpern, W. R., & Cudkowicz, M. E. (2007). Coenzyme Q treatment of neurodegenerative diseases of aging. Mitochondrion, 7, S146–S153.

    Google Scholar 

  • Halliday, G. M., Ophof, A., Broe, M., Jensen, P. H., Kettle, E., Fedorow, H., et al. (2005). Alpha-synuclein redistributes to neuromelanin lipid in the substantia nigra early in Parkinson’s disease. Brain, 128, 2654–2664.

    Article  PubMed  Google Scholar 

  • Hermida-Ameijeiras, A., Mendez-Alvarez, E., Sanchez-Iglesias, S., Sanmartin-Suarez, C., & Soto-Otero, R. (2004). Autoxidation and MAO-mediated metabolism of dopamine as a potential cause of oxidative stress: Role of ferrous and ferric ions. Neurochemistry International, 45, 103–116.

    Article  PubMed  CAS  Google Scholar 

  • Hughes, A. J., Ben-Shlomo, Y., Daniel, S. E., & Lees, A. J. (1992). What features improve the accuracy of clinical diagnosis in Parkinson’s disease? A clinicopathologic study. Neurology, 42, 1142–1146.

    PubMed  CAS  Google Scholar 

  • Isobe, C., Abe, T., & Terayama, Y. (2010). Levels of reduced and oxidized coenzyme Q-10 and 8-hydroxy-2’-deoxyguanosine in the cerebrospinal fluid of patients with living Parkinson’s disease demonstrate that mitochondrial oxidative damage and/or oxidative DNA damage contributes to the neurodegenerative process. Neuroscience Letters, 469, 159–163.

    Google Scholar 

  • Jellinger, K. A. (2000). Cell death mechanisms in Parkinson’s disease. Journal of Neural Transmission, 107, 1–29.

    Article  PubMed  CAS  Google Scholar 

  • Lamberti, P., Zoccolella, S., Iliceto, G., Armenise, E., Fraddosio, A., de Mari, M., et al. (2005). Effects of levodopa and COMT inhibitors on plasma homocysteine in Parkinson’s disease patients. Movement Disorders, 20, 69–72.

    Article  PubMed  Google Scholar 

  • Mattson, M. P., & Shea, T. B. (2003). Folate and homocysteine metabolism in neural plasticity and neurodegenerative disorders. Trends in Neuroscience, 26, 137–146.

    Article  CAS  Google Scholar 

  • Obeid, R., Schadt, A., Dillmann, U., Kostopoulos, P., Fassbender, K., & Herrmann, W. (2009). Methylation status and neurodegenerative markers in Parkinson disease. Clinical Chemistry, 55(10), 1852–1860.

    Article  PubMed  CAS  Google Scholar 

  • O’Suilleabhain, P. E., Oberle, R., Bartis, C., Dewey, R. B., Jr., Bottiglieri, T., & Diaz-Arrastia, R. (2006). Clinical course in Parkinson’s disease with elevated homocysteine. Parkinsonism Related Disorders, 12(2), 103–107.

    Article  PubMed  Google Scholar 

  • O’Suilleabhain, P. E., Sung, V., Hernandez, C., Lacritz, L., Dewey, R. B., Jr., Bottiglieri, T., et al. (2004). Elevated plasma homocysteine level in patients with Parkinson disease: Motor, affective, and cognitive associations. Archives of Neurology, 61, 865–868.

    Article  PubMed  Google Scholar 

  • Palacino, J. J., Sagi, D., Goldberg, M. S., Krauss, S., Motz, C., Wacker, M., et al. (2004). Mitochondrial dysfunction and oxidative damage in parkin-deficient mice. Journal of Biological Chemistry, 279, 18614–18622.

    Article  PubMed  CAS  Google Scholar 

  • Postuma, R. B., & Lang, A. E. (2004). Homocysteine and levodopa. Should Parkinson disease patients receive preventative therapy? Neurology, 63, 886–891.

    PubMed  CAS  Google Scholar 

  • Prigione, A., Begni, B., Galbussera, A., Beretta, S., Brighina, L., Garofalo, R., et al. (2006). Oxidative stress in peripheral blood mononuclear cells from patients with Parkinson’s disease: negative correlation with levodopa dosage. Neurobiological Disease, 23(1), 36–43.

    Article  CAS  Google Scholar 

  • Rajabally, Y. A., & Martey, J. (2011). Neuropathy in Parkinson disease: Prevalence and determinants. Neurology, 77(22), 1947–1950.

    Article  PubMed  Google Scholar 

  • Schneider, J. A., Rees, D. C., Liu, Y. T., & Clegg, J. B. (1998). Worldwide distribution of a common methylenetetrahydrofolate reductase mutation. American Journal of Human Genetics, 62(5), 1258–1260.

    Article  PubMed  CAS  Google Scholar 

  • Shults, C. W., Haas, R. H., Passov, D., & Beal, M. F. (1997). Coenzyme Q10 levels correlate with the activities of the complex I and II/III in mitochondria from parkinsonian and nonparkinsonian subjects. Annals of Neurology, 42, 261–264.

    Article  PubMed  CAS  Google Scholar 

  • Shults, C. W., Oakes, D., Kieburtz, K., et al. (2002). Effects of coenzyme Q-sub-1-sub-0 in early Parkinson disease: Evidence of slowing of the functional decline. Arch Neurology, 59, 1541–1550.

    Article  Google Scholar 

  • Sohmiya, M., Tanaka, M., Tak, N. W., Yanagisawa, M., Tanino, Y., Suzuki, Y., et al. (2004). Redox status of plasma coenzyme Q10 indicates elevated systemic oxidative stress in Parkinson’s disease. Journal of Neurological Sciences, 223, 161–166.

    Article  CAS  Google Scholar 

  • Stephans, S. E., Miller, G. W., Levey, A. I., & Greenamyre, J. T. (2002). Acute mitochondrial and chronic toxicological effects of 1-methyl-4-phenylpyridinium in human neuroblastoma cells. Neurotoxicology, 23(4–5), 569–580.

    Article  PubMed  CAS  Google Scholar 

  • Storch, A., Jost, W. H., Vieregge, P., et al. (2007). (2007) Randomized, double-blind, placebo-controlled trial on symptomatic effects of coenzyme Q10 in Parkinson disease. Arch Neurology, 64(7), 938–944.

    Article  Google Scholar 

  • Todorovic, Z., Dzoljic, E., Novakovic, I., Mirković, D., Stojanović, R., Nesić, Z., et al. (2006). Homocysteine serum levels and MTHFR C677T genotype in patients with Parkinson’s disease, with and without levodopa therapy. Journal of Neurological Sciences, 248, 56–61.

    Article  CAS  Google Scholar 

  • Yamashita, S., & Yamamoto, Y. (1997). Simultaneous detection of ubiquinol and ubiquinone in human plasma as a marker of oxidative stress. Analytical Biochemistry, 250, 66–73.

    Article  PubMed  CAS  Google Scholar 

  • Yasuda, T., Hayakawa, H., Nihira, T., Ren, Y. R., Nakata, Y., Nagai, M., et al. (2011). Parkin-mediated protection of dopaminergic neurons in a chronic MPTP-minipump mouse model of Parkinson disease. Journal of Neuropathology and Experimental Neurology, 70(8), 686–697.

    Article  PubMed  Google Scholar 

  • Yasui, K., Kowa, H., Nakaso, K., Takeshima, T., & Nakashima, K. (2000). Plasma homocysteine and MTHFR C677T genotype in levodopa-treated patients with PD. Neurology, 55, 437–440.

    PubMed  CAS  Google Scholar 

  • Young, A. J., Johnson, S., Steffens, D. C., & Doraiswamy, P. M. (2007, Jan). Coenzyme Q10: A review of its promise as a neuroprotectant. CNS Spectr, 12(1), 62–68.

    Google Scholar 

  • Zoccolella, S., dell’Aquila, C., Abruzzese, G., Antonini, A., Bonuccelli, U., Canesi, M., et al. (2009). Hyperhomocysteinemia in levodopa-treated patients with Parkinson’s disease dementia. Movement Disorders, 24(7), 1028–1033.

    Google Scholar 

  • Zou, C. G., & Banerjee, R. (2005). Homocysteine and redox signaling. Antioxidants & Redox Signaling, 7, 547–559.

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. IRCCS Neurolesi “Bonino-Pulejo”, Messina, Italy

    Gaetano Gorgone

  2. Department of Biochemical, Physiological and Nutritional Sciences, University of Messina, Via Consolare Valeria, Policlinico “G. Martino”, 98125, Messina, Italy

    Monica Currò, Nadia Ferlazzo, Giulia Parisi, Riccardo Ientile & Daniela Caccamo

  3. Department of Neurosciences, University of Messina, Messina, Italy

    Francesco Pisani

  4. Department of Neuroscience, Neurology Clinic, Sant’Anna Hospital, Como, Italy

    Vincenzo Belcastro

  5. Neurologic Clinic, University of Perugia, Perugia, Italy

    Lucilla Parnetti, Nicola Tambasco, Aroldo Rossi & Paolo Calabresi

  6. IRCCS, Foundation Santa Lucia, Rome, Italy

    Paolo Calabresi

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  1. Gaetano Gorgone
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  2. Monica Currò
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Correspondence to Daniela Caccamo.

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Gorgone, G., Currò, M., Ferlazzo, N. et al. Coenzyme Q10, Hyperhomocysteinemia and MTHFR C677T Polymorphism in Levodopa-treated Parkinson’s Disease Patients. Neuromol Med 14, 84–90 (2012). https://doi.org/10.1007/s12017-012-8174-1

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  • DOI: https://doi.org/10.1007/s12017-012-8174-1

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