Opinion
EDITORIAL
Targeting Mitochondria for Neuroprotection in Parkinson Disease Anthony H. V. Schapira, DSc, MD, FRCP, FMedSci; Sandip Patel, PhD
It is now generally accepted that mitochondrial dysfunction plays a significant role in the etiology and pathogenesis of Parkinson disease (PD). Mitochondrial involvement in PD was first identified with specific defects of mitochondrial complex I of the respiratory chain in substantia nigra,1,2 and abnorRelated article page 543 malities of this protein in the brain of individuals with PD have been identified in additional studies of protein expression.3 Significant support for the mitochondrial theory of PD causation has come from the discovery of mutations of mitochondrial proteins as a cause for parkinsonism (eg, PINK1, parkin, and DJ1).4 The mitochondrial defect in PD was an early target for therapeutic intervention. In a small blinded study (ie, the QE2 study) involving 80 patients divided into a placebo group and 3 different dose groups, coenzyme Q10 appeared to demonstrate some potential for slowing disease progression.5 It was on the basis of these results that the QE3 study was designed, and the results of the QE3 study are presented in this issue of the journal.6 The QE3 study was a North American multicenter, randomized, double-blind study evaluating the efficacy of 2 different doses of coenzyme Q10 (1200 and 2400 mg daily) and placebo in approximately 200 participants with early PD per arm. All 3 groups of participants also received 1200 IU of vitamin E because there is evidence that this enhances the effect of coenzyme Q10 in enhancing mitochondrial function. The participants were observed for 16 months or until a disability requiring dopaminergic treatment, whichever occurred first. The primary outcome was the change in total Unified Parkinson’s Disease Rating Scale (UPDRS) score (Parts I-III) from baseline to final visit. The doses of coenzyme Q10 were well tolerated, but at the end of the study, there was no significant difference in the primary end point between either coenzyme Q10 dose and placebo. These results are also in line with those from previous smaller studies.7,8 The participants who were enrolled in the QE3 study had a mean duration of PD since diagnosis of approximately 7 months, a baseline motor UPDRS score in the range of 16.2 to 16.5, and a mean total UPDRS score of 22.7. Over the duration of the study, there was a decrease of 8 points in total UPDRS score, which is equivalent to an annual rate of 6. Two other recent studies have included participants with early PD in a placebo arm, and these studies have shown an annualized rate of progression in early PD of 5.5 to 6.2 points in total UPDRS score.9,10
Coenzyme Q10 has been used to address the mitochondrial defects identified in Huntington disease and Friedreich ataxia. With regard to Huntington disease, there was a trend toward slower progression, but this did not reach significance.11 In Friedreich ataxia, a combination of coenzyme Q10 and vitamin E improved neurological progression compared with 4-year cross-sectional natural progression data,12 and the lowdose therapy was as effective as the high-dose therapy in improving function in those with coexisting coenzyme Q deficiency.13 However, this apparent efficacy, if correct, in Friedreich ataxia may be explained by the primary genetic defect in this disorder involving mutations in the mitochondrial protein frataxin, which result in a severe defect of respiratory chain function.14 The failure of coenzyme Q10 in PD may be explained by a number of factors. These would include the relevance of the mitochondrial defect to the progression of neurodegeneration and the ability of coenzyme Q10 to cross into the brain, and to do so at a sufficient dose to improve mitochondrial and neuronal function, even at a relatively early clinical stage of PD. Other more brain-penetrant forms of coenzyme Q10 (eg, MitoQ) have also failed in an early clinical trial in PD.15 Our understanding of the involvement of mitochondrial defects in neurodegeneration now extends beyond the potential contribution of the bioenergetic defect to include the role of mitochondrial turnover and mitochondrial calcium homeostasis. Parkin and PINK1 proteins play important roles in the identification and tagging of dysfunctional mitochondria for lysosomal degradation (mitophagy).16 Mutations of the corresponding genes impair this activity and result in the accumulation of defective mitochondria and a consequent increase in oxidative stress.17,18 Mitophagy has become an area of interest for the development of potential therapies to slow PD progression by enhancing mitophagy. Upregulation of the translation inhibitor 4E-BP ameliorates the effects of PINK1/ parkin mutants in Drosophila, and rapamycin, a drug that activates 4E-BP and autophagy, is also protective in these mutants.19 Mitochondria act as key hubs coordinating both signaling and cell death pathways. Critical to their function is calcium (Ca2+), which is taken up from the cytosol to match mitochondrial function with cellular energy demand. Excessive Ca2+ uptake results in Ca2+ overload and cell death.20 Pacemaker activity in the substantia nigra neurons is associated with Ca2+ influx across the plasma membrane via voltage-gated Ca2+ channels. These signals are thought to be tempered by mitochondria, thus putting them “at risk” to the ensuing oxida-
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Copyright 2014 American Medical Association. All rights reserved.
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Opinion Editorial
tive stress.21 Indeed, DJ1 may act to offset potential oxidative damage, thus providing a mechanism to explain selective neuronal loss when DJ1 is mutated in PD.22 The Ca2+ signals that derive from the endoplasmic reticulum are also transmitted to mitochondria through close interorganellar contacts—contacts that may be regulated by α-synuclein and other gene products implic ated in PD. 2 3 Lysosomes, although critical for autophagy, are also mobilizable stores of Ca2+ that are both functionally and physically coupled to endoplasmic reticulum Ca2+ stores.24 In this context, LRRK2 has been shown to modulate autophagy through a Ca 2+ dependent pathway involving nicotinic acid adenine dinucleotide phosphate, 25 which “triggers” Ca 2+ release from lysosomes and other acidic organelles through the recently described endolysosomal 2-pore channels. 26 In turn, these signals are likely received by mitochondria following amplification by the endoplasmic reticulum. Thus, targeting of Ca 2+ pathways that ultimately converge on ARTICLE INFORMATION Author Affiliations: Department of Clinical Neurosciences, Institute of Neurology, University College London, London, England (Schapira); Department of Cell and Developmental Biology, University College London, London, England (Patel).
symptomatic effects of coenzyme Q(10) in Parkinson disease. Arch Neurol. 2007;64(7): 938-944.
18. Gegg ME, Schapira AH. PINK1-parkindependent mitophagy involves ubiquitination of mitofusins 1 and 2. Autophagy. 2011;7(2):243-245.
8. NINDS NET-PD Investigators. A randomized clinical trial of coenzyme Q10 and GPI-1485 in early Parkinson disease. Neurology. 2007;68(1):20-28.
19. Tain LS, Mortiboys H, Tao RN, Ziviani E, Bandmann O, Whitworth AJ. Rapamycin activation of 4E-BP prevents parkinsonian dopaminergic neuron loss. Nat Neurosci. 2009;12(9):1129-1135.
9. Schapira AH, McDermott MP, Barone P, et al. Pramipexole in patients with early Parkinson’s disease (PROUD). Lancet Neurol. 2013;12(8): 747-755.
20. Duchen MR, Szabadkai G. Roles of mitochondria in human disease. Essays Biochem. 2010;47:115-137.
10. Olanow CW, Rascol O, Hauser R, et al; ADAGIO Study Investigators. A double-blind, delayed-start trial of rasagiline in Parkinson's disease. N Engl J Med. 2009;361(13):1268-1278.
21. Guzman JN, Sánchez-Padilla J, Chan CS, Surmeier DJ. Robust pacemaking in substantia nigra dopaminergic neurons. J Neurosci. 2009;29(35):11011-11019.
11. Huntington Study Group. A randomized, placebo-controlled trial of coenzyme Q10 and remacemide in Huntington’s disease. Neurology. 2001;57(3):397-404.
22. Guzman JN, Sanchez-Padilla J, Wokosin D, et al. Oxidant stress evoked by pacemaking in dopaminergic neurons is attenuated by DJ-1. Nature. 2010;468(7324):696-700.
12. Hart PE, Lodi R, Rajagopalan B, et al. Antioxidant treatment of patients with Friedreich ataxia. Arch Neurol. 2005;62(4):621-626.
23. Calì T, Ottolini D, Brini M. Mitochondrial Ca(2+) and neurodegeneration. Cell Calcium. 2012;52(1):73-85.
2. Schapira AH, Cooper JM, Dexter D, Clark JB, Jenner P, Marsden CD. Mitochondrial complex I deficiency in Parkinson’s disease. J Neurochem. 1990;54(3):823-827.
13. Cooper JM, Korlipara LV, Hart PE, Bradley JL, Schapira AH. Coenzyme Q10 and vitamin E deficiency in Friedreich’s ataxia. Eur J Neurol. 2008;15(12):1371-1379.
24. Kilpatrick BS, Eden ER, Schapira AH, Futter CE, Patel S. Direct mobilisation of lysosomal Ca2+ triggers complex Ca2+ signals. J Cell Sci. 2013;126(pt 1):60-66.
3. Schapira AH. Mitochondria in the aetiology and pathogenesis of Parkinson’s disease. Lancet Neurol. 2008;7(1):97-109.
14. Bradley JL, Blake JC, Chamberlain S, Thomas PK, Cooper JM, Schapira AH. Clinical, biochemical and molecular genetic correlations in Friedreich’s ataxia. Hum Mol Genet. 2000;9(2):275-282.
25. Gómez-Suaga P, Luzón-Toro B, Churamani D, et al. Leucine-rich repeat kinase 2 regulates autophagy through a calcium-dependent pathway involving NAADP. Hum Mol Genet. 2012;21(3):511-525.
Corresponding Author: Anthony H. V. Schapira, DSc, MD, FRCP, FMedSci, Department of Clinical Neurosciences, Institute of Neurology, University College London, Rowland Hill St, London NW3 2PF, England. Published Online: March 24, 2014. doi:10.1001/jamaneurol.2014.64. Conflict of Interest Disclosures: None reported. REFERENCES 1. Schapira AH, Cooper JM, Dexter D, Jenner P, Clark JB, Marsden CD. Mitochondrial complex I deficiency in Parkinson’s disease. Lancet. 1989;1(8649):1269.
4. Houlden H, Singleton AB. The genetics and neuropathology of Parkinson’s disease. Acta Neuropathol. 2012;124(3):325-338. 5. Shults CW, Oakes D, Kieburtz K, et al; Parkinson Study Group. Effects of coenzyme Q10 in early Parkinson disease. Arch Neurol. 2002;59(10):15411550. 6. The Parkinson Study Group QE3 Investigators. A randomized clinical trial of high-dosage coenzyme Q10 in early Parkinson disease: no evidence of benefit [published online March 24, 2014]. JAMA Neurol. doi:10.1001/jamaneurol.2014.131. 7. Storch A, Jost WH, Vieregge P, et al; German Coenzyme Q(10) Study Group. Randomized, double-blind, placebo-controlled trial on
538
mitochondria may represent attractive loci for early therapeutic intervention in PD. Of note, the use of L-type Ca2+ channel antagonists that are clinically approved for treatment of hypertension is being actively pursued.27 Is this the end of the road for coenzyme Q10 in PD? The QE3 trial provides an unequivocal “yes” as the answer. The findings should encourage physicians to dissuade patients from investing in its use as a potential drug to slow the progression of PD. Is this the end of the road for targeting mitochondria for neuroprotection in PD? Our answer to this would be an unequivocal “no.” Substantial advances have been made in recent years in our understanding of the etiopathogenesis of PD. In particular, the role of mitochondria, mitophagy, and possibly Ca2+ dysfunction are seen to be key to the initiation and progression of neurodegeneration.28,29 These new mitochondrial pathways are currently being targeted for the development of potential interventions to slow PD progression.
15. Snow BJ, Rolfe FL, Lockhart MM, et al; Protect Study Group. A double-blind, placebo-controlled study to assess the mitochondria-targeted antioxidant MitoQ as a disease-modifying therapy in Parkinson’s disease. Mov Disord. 2010;25(11):1670-1674. 16. Cho DH, Nakamura T, Lipton SA. Mitochondrial dynamics in cell death and neurodegeneration. Cell Mol Life Sci. 2010;67(20):3435-3447. 17. Gegg ME, Cooper JM, Chau KY, Rojo M, Schapira AH, Taanman JW. Mitofusin 1 and mitofusin 2 are ubiquitinated in a PINK1/parkin-dependent manner upon induction of mitophagy. Hum Mol Genet. 2010;19(24):4861-4870.
26. Patel S, Marchant JS, Brailoiu E. Two-pore channels. Cell Calcium. 2010;47(6):480-490. 27. Parkinson Study Group. Phase II safety, tolerability, and dose selection study of isradipine as a potential disease-modifying intervention in early Parkinson’s disease (STEADY-PD). Mov Disord. 2013;28(13):1823-1831. 28. Schapira AH, Olanow CW, Greenamyre JT, Bezard E. Slowing neurodegeneration in Parkinson’s disease and Huntington’s disease: therapeutic perspective. Lancet. In press. 29. Schapira AH. Calcium dysregulation in Parkinson’s disease. Brain. 2013;136(pt 7):2015-2016.
JAMA Neurology May 2014 Volume 71, Number 5
Copyright 2014 American Medical Association. All rights reserved.
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jamaneurology.com
EDITORIAL
Targeting Mitochondria for Neuroprotection in Parkinson Disease Anthony H. V. Schapira, DSc, MD, FRCP, FMedSci; Sandip Patel, PhD
It is now generally accepted that mitochondrial dysfunction plays a significant role in the etiology and pathogenesis of Parkinson disease (PD). Mitochondrial involvement in PD was first identified with specific defects of mitochondrial complex I of the respiratory chain in substantia nigra,1,2 and abnorRelated article page 543 malities of this protein in the brain of individuals with PD have been identified in additional studies of protein expression.3 Significant support for the mitochondrial theory of PD causation has come from the discovery of mutations of mitochondrial proteins as a cause for parkinsonism (eg, PINK1, parkin, and DJ1).4 The mitochondrial defect in PD was an early target for therapeutic intervention. In a small blinded study (ie, the QE2 study) involving 80 patients divided into a placebo group and 3 different dose groups, coenzyme Q10 appeared to demonstrate some potential for slowing disease progression.5 It was on the basis of these results that the QE3 study was designed, and the results of the QE3 study are presented in this issue of the journal.6 The QE3 study was a North American multicenter, randomized, double-blind study evaluating the efficacy of 2 different doses of coenzyme Q10 (1200 and 2400 mg daily) and placebo in approximately 200 participants with early PD per arm. All 3 groups of participants also received 1200 IU of vitamin E because there is evidence that this enhances the effect of coenzyme Q10 in enhancing mitochondrial function. The participants were observed for 16 months or until a disability requiring dopaminergic treatment, whichever occurred first. The primary outcome was the change in total Unified Parkinson’s Disease Rating Scale (UPDRS) score (Parts I-III) from baseline to final visit. The doses of coenzyme Q10 were well tolerated, but at the end of the study, there was no significant difference in the primary end point between either coenzyme Q10 dose and placebo. These results are also in line with those from previous smaller studies.7,8 The participants who were enrolled in the QE3 study had a mean duration of PD since diagnosis of approximately 7 months, a baseline motor UPDRS score in the range of 16.2 to 16.5, and a mean total UPDRS score of 22.7. Over the duration of the study, there was a decrease of 8 points in total UPDRS score, which is equivalent to an annual rate of 6. Two other recent studies have included participants with early PD in a placebo arm, and these studies have shown an annualized rate of progression in early PD of 5.5 to 6.2 points in total UPDRS score.9,10
Coenzyme Q10 has been used to address the mitochondrial defects identified in Huntington disease and Friedreich ataxia. With regard to Huntington disease, there was a trend toward slower progression, but this did not reach significance.11 In Friedreich ataxia, a combination of coenzyme Q10 and vitamin E improved neurological progression compared with 4-year cross-sectional natural progression data,12 and the lowdose therapy was as effective as the high-dose therapy in improving function in those with coexisting coenzyme Q deficiency.13 However, this apparent efficacy, if correct, in Friedreich ataxia may be explained by the primary genetic defect in this disorder involving mutations in the mitochondrial protein frataxin, which result in a severe defect of respiratory chain function.14 The failure of coenzyme Q10 in PD may be explained by a number of factors. These would include the relevance of the mitochondrial defect to the progression of neurodegeneration and the ability of coenzyme Q10 to cross into the brain, and to do so at a sufficient dose to improve mitochondrial and neuronal function, even at a relatively early clinical stage of PD. Other more brain-penetrant forms of coenzyme Q10 (eg, MitoQ) have also failed in an early clinical trial in PD.15 Our understanding of the involvement of mitochondrial defects in neurodegeneration now extends beyond the potential contribution of the bioenergetic defect to include the role of mitochondrial turnover and mitochondrial calcium homeostasis. Parkin and PINK1 proteins play important roles in the identification and tagging of dysfunctional mitochondria for lysosomal degradation (mitophagy).16 Mutations of the corresponding genes impair this activity and result in the accumulation of defective mitochondria and a consequent increase in oxidative stress.17,18 Mitophagy has become an area of interest for the development of potential therapies to slow PD progression by enhancing mitophagy. Upregulation of the translation inhibitor 4E-BP ameliorates the effects of PINK1/ parkin mutants in Drosophila, and rapamycin, a drug that activates 4E-BP and autophagy, is also protective in these mutants.19 Mitochondria act as key hubs coordinating both signaling and cell death pathways. Critical to their function is calcium (Ca2+), which is taken up from the cytosol to match mitochondrial function with cellular energy demand. Excessive Ca2+ uptake results in Ca2+ overload and cell death.20 Pacemaker activity in the substantia nigra neurons is associated with Ca2+ influx across the plasma membrane via voltage-gated Ca2+ channels. These signals are thought to be tempered by mitochondria, thus putting them “at risk” to the ensuing oxida-
jamaneurology.com
JAMA Neurology May 2014 Volume 71, Number 5
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archneur.jamanetwork.com/ by a Tulane University User on 05/17/2015
537
Opinion Editorial
tive stress.21 Indeed, DJ1 may act to offset potential oxidative damage, thus providing a mechanism to explain selective neuronal loss when DJ1 is mutated in PD.22 The Ca2+ signals that derive from the endoplasmic reticulum are also transmitted to mitochondria through close interorganellar contacts—contacts that may be regulated by α-synuclein and other gene products implic ated in PD. 2 3 Lysosomes, although critical for autophagy, are also mobilizable stores of Ca2+ that are both functionally and physically coupled to endoplasmic reticulum Ca2+ stores.24 In this context, LRRK2 has been shown to modulate autophagy through a Ca 2+ dependent pathway involving nicotinic acid adenine dinucleotide phosphate, 25 which “triggers” Ca 2+ release from lysosomes and other acidic organelles through the recently described endolysosomal 2-pore channels. 26 In turn, these signals are likely received by mitochondria following amplification by the endoplasmic reticulum. Thus, targeting of Ca 2+ pathways that ultimately converge on ARTICLE INFORMATION Author Affiliations: Department of Clinical Neurosciences, Institute of Neurology, University College London, London, England (Schapira); Department of Cell and Developmental Biology, University College London, London, England (Patel).
symptomatic effects of coenzyme Q(10) in Parkinson disease. Arch Neurol. 2007;64(7): 938-944.
18. Gegg ME, Schapira AH. PINK1-parkindependent mitophagy involves ubiquitination of mitofusins 1 and 2. Autophagy. 2011;7(2):243-245.
8. NINDS NET-PD Investigators. A randomized clinical trial of coenzyme Q10 and GPI-1485 in early Parkinson disease. Neurology. 2007;68(1):20-28.
19. Tain LS, Mortiboys H, Tao RN, Ziviani E, Bandmann O, Whitworth AJ. Rapamycin activation of 4E-BP prevents parkinsonian dopaminergic neuron loss. Nat Neurosci. 2009;12(9):1129-1135.
9. Schapira AH, McDermott MP, Barone P, et al. Pramipexole in patients with early Parkinson’s disease (PROUD). Lancet Neurol. 2013;12(8): 747-755.
20. Duchen MR, Szabadkai G. Roles of mitochondria in human disease. Essays Biochem. 2010;47:115-137.
10. Olanow CW, Rascol O, Hauser R, et al; ADAGIO Study Investigators. A double-blind, delayed-start trial of rasagiline in Parkinson's disease. N Engl J Med. 2009;361(13):1268-1278.
21. Guzman JN, Sánchez-Padilla J, Chan CS, Surmeier DJ. Robust pacemaking in substantia nigra dopaminergic neurons. J Neurosci. 2009;29(35):11011-11019.
11. Huntington Study Group. A randomized, placebo-controlled trial of coenzyme Q10 and remacemide in Huntington’s disease. Neurology. 2001;57(3):397-404.
22. Guzman JN, Sanchez-Padilla J, Wokosin D, et al. Oxidant stress evoked by pacemaking in dopaminergic neurons is attenuated by DJ-1. Nature. 2010;468(7324):696-700.
12. Hart PE, Lodi R, Rajagopalan B, et al. Antioxidant treatment of patients with Friedreich ataxia. Arch Neurol. 2005;62(4):621-626.
23. Calì T, Ottolini D, Brini M. Mitochondrial Ca(2+) and neurodegeneration. Cell Calcium. 2012;52(1):73-85.
2. Schapira AH, Cooper JM, Dexter D, Clark JB, Jenner P, Marsden CD. Mitochondrial complex I deficiency in Parkinson’s disease. J Neurochem. 1990;54(3):823-827.
13. Cooper JM, Korlipara LV, Hart PE, Bradley JL, Schapira AH. Coenzyme Q10 and vitamin E deficiency in Friedreich’s ataxia. Eur J Neurol. 2008;15(12):1371-1379.
24. Kilpatrick BS, Eden ER, Schapira AH, Futter CE, Patel S. Direct mobilisation of lysosomal Ca2+ triggers complex Ca2+ signals. J Cell Sci. 2013;126(pt 1):60-66.
3. Schapira AH. Mitochondria in the aetiology and pathogenesis of Parkinson’s disease. Lancet Neurol. 2008;7(1):97-109.
14. Bradley JL, Blake JC, Chamberlain S, Thomas PK, Cooper JM, Schapira AH. Clinical, biochemical and molecular genetic correlations in Friedreich’s ataxia. Hum Mol Genet. 2000;9(2):275-282.
25. Gómez-Suaga P, Luzón-Toro B, Churamani D, et al. Leucine-rich repeat kinase 2 regulates autophagy through a calcium-dependent pathway involving NAADP. Hum Mol Genet. 2012;21(3):511-525.
Corresponding Author: Anthony H. V. Schapira, DSc, MD, FRCP, FMedSci, Department of Clinical Neurosciences, Institute of Neurology, University College London, Rowland Hill St, London NW3 2PF, England. Published Online: March 24, 2014. doi:10.1001/jamaneurol.2014.64. Conflict of Interest Disclosures: None reported. REFERENCES 1. Schapira AH, Cooper JM, Dexter D, Jenner P, Clark JB, Marsden CD. Mitochondrial complex I deficiency in Parkinson’s disease. Lancet. 1989;1(8649):1269.
4. Houlden H, Singleton AB. The genetics and neuropathology of Parkinson’s disease. Acta Neuropathol. 2012;124(3):325-338. 5. Shults CW, Oakes D, Kieburtz K, et al; Parkinson Study Group. Effects of coenzyme Q10 in early Parkinson disease. Arch Neurol. 2002;59(10):15411550. 6. The Parkinson Study Group QE3 Investigators. A randomized clinical trial of high-dosage coenzyme Q10 in early Parkinson disease: no evidence of benefit [published online March 24, 2014]. JAMA Neurol. doi:10.1001/jamaneurol.2014.131. 7. Storch A, Jost WH, Vieregge P, et al; German Coenzyme Q(10) Study Group. Randomized, double-blind, placebo-controlled trial on
538
mitochondria may represent attractive loci for early therapeutic intervention in PD. Of note, the use of L-type Ca2+ channel antagonists that are clinically approved for treatment of hypertension is being actively pursued.27 Is this the end of the road for coenzyme Q10 in PD? The QE3 trial provides an unequivocal “yes” as the answer. The findings should encourage physicians to dissuade patients from investing in its use as a potential drug to slow the progression of PD. Is this the end of the road for targeting mitochondria for neuroprotection in PD? Our answer to this would be an unequivocal “no.” Substantial advances have been made in recent years in our understanding of the etiopathogenesis of PD. In particular, the role of mitochondria, mitophagy, and possibly Ca2+ dysfunction are seen to be key to the initiation and progression of neurodegeneration.28,29 These new mitochondrial pathways are currently being targeted for the development of potential interventions to slow PD progression.
15. Snow BJ, Rolfe FL, Lockhart MM, et al; Protect Study Group. A double-blind, placebo-controlled study to assess the mitochondria-targeted antioxidant MitoQ as a disease-modifying therapy in Parkinson’s disease. Mov Disord. 2010;25(11):1670-1674. 16. Cho DH, Nakamura T, Lipton SA. Mitochondrial dynamics in cell death and neurodegeneration. Cell Mol Life Sci. 2010;67(20):3435-3447. 17. Gegg ME, Cooper JM, Chau KY, Rojo M, Schapira AH, Taanman JW. Mitofusin 1 and mitofusin 2 are ubiquitinated in a PINK1/parkin-dependent manner upon induction of mitophagy. Hum Mol Genet. 2010;19(24):4861-4870.
26. Patel S, Marchant JS, Brailoiu E. Two-pore channels. Cell Calcium. 2010;47(6):480-490. 27. Parkinson Study Group. Phase II safety, tolerability, and dose selection study of isradipine as a potential disease-modifying intervention in early Parkinson’s disease (STEADY-PD). Mov Disord. 2013;28(13):1823-1831. 28. Schapira AH, Olanow CW, Greenamyre JT, Bezard E. Slowing neurodegeneration in Parkinson’s disease and Huntington’s disease: therapeutic perspective. Lancet. In press. 29. Schapira AH. Calcium dysregulation in Parkinson’s disease. Brain. 2013;136(pt 7):2015-2016.
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