Photo of David K. Simon,  MD, PhD

David K. Simon, MD, PhD

Beth Israel Deaconess Medical Center

Beth Israel Deaconess Medical Center
Phone: (617) 735-3251
Fax: (617) 735-2826


dsimon1@bidmc.harvard.edu

David K. Simon, MD, PhD

Beth Israel Deaconess Medical Center

EDUCATIONAL TITLES

  • Associate Professor, Neurology, Harvard Medical School
  • Staff Neurologist, Neurology, Beth Israel Deaconess Medical Center
  • Staff Physician, Neurology, Beth Israel Deaconess Medical Center

DF/HCC PROGRAM AFFILIATION

Research Abstract

Oxidative damage to DNA accumulates with age in the brain, particularly in mitochondrial DNA (mtDNA). Oxidatively DNA damage can induce point mutations. mtDNA point mutations accumulate with age in the brain, with mutation levels correlating inversely with mitochondrial function. Somatic mtDNA point mutations also accumulate within certain cancers. We are studying the accumulation of mtDNA point mutations in single neurons in the brain and the potential role of these mutations in aging and age-related neurodegeneration. In addition, we are studying the role of mitophagy and the mTOR pathway in regulating levels of somatic mtDNA mutations. These data have potential relevance to aging, age-related neurodegenerative disorders, and cancer.

Publications

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  • Taylor KM, Saint-Hilaire MH, Sudarsky L, Simon DK, Hersh B, Sparrow D, Hu H, Weisskopf MG. Head injury at early ages is associated with risk of Parkinson's disease. 2016; 23:57-61. PubMed
  • Clark-Matott J, Saleem A, Dai Y, Shurubor Y, Ma X, Safdar A, Beal MF, Tarnopolsky M, Simon DK. Metabolomic analysis of exercise effects in the POLG mitochondrial DNA mutator mouse brain. Neurobiol Aging 2015. PubMed
  • Stephen CD, Rojas R, Lioutas VA, Papavassiliou E, Simon DK. Complicated spontaneous intracranial hypotension treated with intrathecal saline infusion. Pract Neurol 2015. PubMed
  • Simon DK, Simuni T, Elm J, Clark-Matott J, Graebner AK, Baker L, Dunlop SR, Emborg M, Kamp C, Morgan JC, Ross GW, Sharma S, Ravina B. Peripheral Biomarkers of Parkinson's Disease Progression and Pioglitazone Effects. J Parkinsons Dis 2015. PubMed
  • , Kieburtz K, Tilley BC, Elm JJ, Babcock D, Hauser R, Ross GW, Augustine AH, Augustine EU, Aminoff MJ, Bodis-Wollner IG, Boyd J, Cambi F, Chou K, Christine CW, Cines M, Dahodwala N, Derwent L, Dewey RB, Hawthorne K, Houghton DJ, Kamp C, Leehey M, Lew MF, Liang GS, Luo ST, Mari Z, Morgan JC, Parashos S, Pérez A, Petrovitch H, Rajan S, Reichwein S, Roth JT, Schneider JS, Shannon KM, Simon DK, Simuni T, Singer C, Sudarsky L, Tanner CM, Umeh CC, Williams K, Wills AM. Effect of creatine monohydrate on clinical progression in patients with Parkinson disease: a randomized clinical trial. JAMA 2015; 313:584-93. PubMed
  • , Beal MF, Oakes D, Shoulson I, Henchcliffe C, Galpern WR, Haas R, Juncos JL, Nutt JG, Voss TS, Ravina B, Shults CM, Helles K, Snively V, Lew MF, Griebner B, Watts A, Gao S, Pourcher E, Bond L, Kompoliti K, Agarwal P, Sia C, Jog M, Cole L, Sultana M, Kurlan R, Richard I, Deeley C, Waters CH, Figueroa A, Arkun A, Brodsky M, Ondo WG, Hunter CB, Jimenez-Shahed J, Palao A, Miyasaki JM, So J, Tetrud J, Reys L, Smith K, Singer C, Blenke A, Russell DS, Cotto C, Friedman JH, Lannon M, Zhang L, Drasby E, Kumar R, Subramanian T, Ford DS, Grimes DA, Cote D, Conway J, Siderowf AD, Evatt ML, Sommerfeld B, Lieberman AN, Okun MS, Rodriguez RL, Merritt S, Swartz CL, Martin WR, King P, Stover N, Guthrie S, Watts RL, Ahmed A, Fernandez HH, Winters A, Mari Z, Dawson TM, Dunlop B, Feigin AS, Shannon B, Nirenberg MJ, Ogg M, Ellias SA, Thomas CA, Frei K, Bodis-Wollner I, Glazman S, Mayer T, Hauser RA, Pahwa R, Langhammer A, Ranawaya R, Derwent L, Sethi KD, Farrow B, Prakash R, Litvan I, Robinson A, Sahay A, Gartner M, Hinson VK, Markind S, Pelikan M, Perlmutter JS, Hartlein J, Molho E, Evans S, Adler CH, Duffy A, Lind M, Elmer L, Davis K, Spears J, Wilson S, Leehey MA, Hermanowicz N, Niswonger S, Shill HA, Obradov S, Rajput A, Cowper M, Lessig S, Song D, Fontaine D, Zadikoff C, Williams K, Blindauer KA, Bergholte J, Propsom CS, Stacy MA, Field J, Mihaila D, Chilton M, Uc EY, Sieren J, Simon DK, Kraics L, Silver A, Boyd JT, Hamill RW, Ingvoldstad C, Young J, Thomas K, Kostyk SK, Wojcieszek J, Pfeiffer RF, Panisset M, Beland M, Reich SG, Cines M, Zappala N, Rivest J, Zweig R, Lumina LP, Hilliard CL, Grill S, Kellermann M, Tuite P, Rolandelli S, Kang UJ, Young J, Rao J, Cook MM, Severt L, Boyar K. A Randomized Clinical Trial of High-Dosage Coenzyme Q10 in Early Parkinson Disease: No Evidence of Benefit. JAMA Neurol 2014. PubMed
  • Dai Y, Zheng K, Clark J, Swerdlow RH, Pulst SM, Sutton JP, Shinobu LA, Simon DK. Rapamycin drives selection against a pathogenic heteroplasmic mitochondrial DNA mutation. Hum Mol Genet 2014; 23:637-47. PubMed
  • Umeh CC, Pérez A, Augustine EF, Dhall R, Dewey RB, Mari Z, Simon DK, Wills AM, Christine CW, Schneider JS, Suchowersky O. No sex differences in use of dopaminergic medication in early Parkinson disease in the US and Canada - baseline findings of a multicenter trial. PLoS ONE 2014; 9:e112287. PubMed
  • Austin MD, Simon DK, Betensky RA. Computationally simple estimation and improved efficiency for special cases of double truncation. Lifetime Data Analysis 2013. PubMed
  • Dai Y, Kiselak T, Clark J, Clore E, Zheng K, Cheng A, Kujoth GC, Prolla TA, Maratos-Flier E, Simon DK. Behavioral and metabolic characterization of heterozygous and homozygous POLG mutator mice. 2013; 13:282-91. PubMed
  • Demetrius LA, Simon DK. The inverse association of cancer and Alzheimer's: a bioenergetic mechanism. J R Soc Interface 2013; 10:20130006. PubMed
  • Göbel A, Macklin EA, Winkler S, Betensky RA, Klein C, Lohmann K, Simon DK. Genetic risk factors in Parkinson's disease: single gene effects and interactions of genotypes. J Neurol 2012; 259:2503-5. PubMed
  • Demetrius LA, Simon DK. An inverse-Warburg effect and the origin of Alzheimer's disease. Biogerontology 2012. PubMed
  • Kumar KR, Weissbach A, Heldmann M, Kasten M, Tunc S, Sue CM, Svetel M, Kostić VS, Segura-Aguilar J, Ramirez A, Simon DK, Vieregge P, Münte TF, Hagenah J, Klein C, Lohmann K. Frequency of the D620N Mutation in VPS35 in Parkinson Disease. Arch Neurol 2012. PubMed
  • Lin MT, Cantuti-Castelvetri I, Zheng K, Jackson KE, Tan YB, Arzberger T, Lees AJ, Betensky RA, Beal MF, Simon DK. Somatic mitochondrial DNA mutations in early Parkinson and incidental Lewy body disease. Ann Neurol 2012; 71:850-4. PubMed
  • Shih LC, Piel J, Warren A, Kraics L, Silver A, Vanderhorst V, Simon DK, Tarsy D. Singing in groups for Parkinson's disease (SING-PD): A pilot study of group singing therapy for PD-related voice/speech disorders. 2012. PubMed
  • Pankratz N, Beecham GW, Destefano AL, Dawson TM, Doheny KF, Factor SA, Hamza TH, Hung AY, Hyman BT, Ivinson AJ, Krainc D, Latourelle JC, Clark LN, Marder K, Martin ER, Mayeux R, Ross OA, Scherzer CR, Simon DK, Tanner C, Vance JM, Wszolek ZK, Zabetian CP, Myers RH, Payami H, Scott WK, Foroud T, . Meta-analysis of Parkinson's Disease: Identification of a novel locus, RIT2. Ann Neurol 2012; 71:370-84. PubMed
  • Clark J, Silvaggi JM, Kiselak T, Zheng K, Clore EL, Dai Y, Bass CE, Simon DK. Pgc-1α overexpression downregulates Pitx3 and increases susceptibility to MPTP toxicity associated with decreased Bdnf. PLoS ONE 2012; 7:e48925. PubMed
  • Simon DK, Chu CT, Swerdlow RH. Mitochondria and Parkinson's disease. Parkinsons Dis 2012; 2011:261791. PubMed
  • Clark J, Dai Y, Simon DK. Do somatic mitochondrial DNA mutations contribute to Parkinson's disease? Parkinsons Dis 2011; 2011:659694. PubMed
  • Clark J, Reddy S, Zheng K, Betensky RA, Simon DK. Association of PGC-1alpha polymorphisms with age of onset and risk of Parkinson's disease. BMC Med Genet 2011; 12:69. PubMed
  • Connolly BS, Feigenbaum AS, Robinson BH, Dipchand AI, Simon DK, Tarnopolsky MA. Melas Syndrome, Cardiomyopathy, Rhabdomyolysis, and Autism Associated with the A3260g Mitochondrial Dna Mutation. Biochem Biophys Res Commun 2010. PubMed
  • Weisskopf MG, Weuve J, Nie H, Saint-Hilaire MH, Sudarsky L, Simon DK, Hersh B, Schwartz J, Wright RO, Hu H. Association of Cumulative Lead Exposure with Parkinson's Disease. Environ Health Perspect 2010. PubMed
  • Xiao J, Zhao Y, Bastian RW, Perlmutter JS, Racette BA, Tabbal SD, Karimi M, Paniello R, Blitzer A, Batish SD, Wszolek ZK, Uitti RJ, Van Gerpen JA, Hedera P, Simon DK, Tarsy D, Truong DD, Frei KP, Pfeiffer RF, Gong S, LeDoux MS. Novel human pathological mutations. Gene symbol: THAP1. Disease: dystonia 6. Hum Genet 2011; 127:470. PubMed
  • Xiao J, Bastian RW, Perlmutter JS, Racette BA, Tabbal SD, Karimi M, Paniello R, Blitzer A, Batish SD, Wszolek ZK, Uitti RJ, Van Gerpen JA, Hedera P, Simon DK, Tarsy D, Truong DD, Frei KP, Pfeiffer RF, Gong S, LeDoux MS. Novel human pathological mutations. Gene symbol: THAP1. Disease: dystonia 6. Hum Genet 2011; 127:470. PubMed
  • Clark J, Clore EL, Zheng K, Adame A, Masliah E, Simon DK. Oral N-acetyl-cysteine attenuates loss of dopaminergic terminals in alpha-synuclein overexpressing mice. PLoS ONE 2010. PubMed
  • Simon DK, Pankratz N, Kissell DK, Pauciulo MW, Halter CA, Rudolph A, Pfeiffer RF, Nichols WC, Foroud T, . Maternal inheritance and mitochondrial DNA variants in familial Parkinson's disease. BMC Med Genet 2010; 11:53. PubMed
  • Sikorska M, Sandhu JK, Simon DK, Pathiraja V, Sodja C, Li Y, Ribecco-Lutkiewicz M, Lanthier P, Borowy-Borowski H, Upton A, Raha S, Pulst SM, Tarnopolsky MA. Identification of ataxia-associated mtDNA mutations (m.4052T>C and m.9035T>C) and evaluation of their pathogenicity in transmitochondrial cybrids. Muscle Nerve 2009; 40:381-94. PubMed
  • Kraytsberg Y,Simon DK,Turnbull DM,Khrapko K. Do mtDNA deletions drive premature aging in mtDNA mutator mice? Aging Cell 2009; 8:502-6. PubMed
  • Clark J, Simon DK. Transcribe to survive: transcriptional control of antioxidant defense programs for neuroprotection in Parkinson's disease. Antioxid Redox Signal 2009; 11:509-28. PubMed
  • Xiao J,Bastian RW,Perlmutter JS,Racette BA,Tabbal SD,Karimi M,Paniello RC,Blitzer A,Batish SD,Wszolek ZK,Uitti RJ,Hedera P,Simon DK,Tarsy D,Truong DD,Frei KP,Pfeiffer RF,Gong S,Zhao Y,LeDoux MS. High-throughput mutational analysis of TOR1A in primary dystonia. BMC Med Genet 2009; 10:24. PubMed
  • Tarsy D,Simon DK. Beating a dead horse: dopamine and Parkinson disease. Neurology 2008; 71:1651; author reply 1651-2. PubMed
  • Simon DK,Swearingen CJ,Hauser RA,Trugman JM,Aminoff MJ,Singer C,Truong D,Tilley BC. Caffeine and progression of Parkinson disease. Clin Neuropharmacol 2008; 31:189-96. PubMed
  • Wu AD, Fregni F, Simon DK, Deblieck C, Pascual-Leone A. Noninvasive brain stimulation for Parkinson's disease and dystonia. 2008; 5:345-61. PubMed
  • Djarmati A, Guzvic M, Gr. Rapid and reliable detection of exon rearrangements in various movement disorders genes by multiplex ligation-dependent probe amplification. Mov Disord 2007; 22:1708-14. PubMed
  • Simon DK, Zheng K, Vel. Mitochondrial complex I gene variant associated with early age at onset in spinocerebellar ataxia type 2. Arch Neurol 2007; 64:1042-4. PubMed
  • St-Pierre J, Drori S, Uldry M, Silvaggi JM, Rhee J, J. Suppression of reactive oxygen species and neurodegeneration by the PGC-1 transcriptional coactivators. Cell 2006; 127:397-408. PubMed
  • Tarsy D, Simon DK. Dystonia. N Engl J Med 2006; 355:818-29. PubMed
  • Guo X, Kudryavtseva E, Bodyak N, Nicholas A, Dombrovsky I, Yang D, Kraytsberg Y, Simon DK, Khrapko K. Mitochondrial DNA deletions in mice in men: Substantia nigra is much less affected in the mouse. Biochim Biophys Acta 2010; 1797:1159-1162. PubMed
  • Dai Y, Clark J, Zheng K, Kujoth GC, Prolla TA, Simon DK. Somatic mitochondrial DNA mutations do not increase neuronal vulnerability to MPTP in young POLG mutator mice. Neurotoxicol Teratol 2015; 46:62-7. PubMed
  • Simon DK, Wu C, Tilley BC, Wills AM, Aminoff MJ, Bainbridge J, Hauser RA, Schneider JS, Sharma S, Singer C, Tanner CM, Truong D, Wong PS. Caffeine and Progression of Parkinson Disease: A Deleterious Interaction With Creatine. Clin Neuropharmacol 2015; 38:163-9. PubMed
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