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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  • 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
  • Demetrius LA, Simon DK. The inverse association of cancer and Alzheimer's: a bioenergetic mechanism. J R Soc Interface 2013; 10:20130006. 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; 13:282-291. 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
  • 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
  • Clark J, Silvaggi JM, Kiselak T, Zheng K, Clore EL, Dai Y, Bass CE, Simon DK. Pgc-1留 Overexpression Downregulates Pitx3 and Increases Susceptibility to MPTP Toxicity Associated with Decreased Bdnf. PLoS ONE 2012; 7:e48925. 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • Lee J, Kim CH, Simon DK, Aminova L, Andreyev A, Kushnareva Y, Murphy AA, Lonze BE, Kim KS, Ginty DD, Ferrante RJ, Ryu H, Ratan RR. Mitochondrial creb mediates mitochondrial gene expression and neuronal survival. J Biol Chem 2005; 280:40398-401. PubMed
  • Cantuti-Castelvetri I, Lin MT, Zheng K, Keller-McGandy CE, Betensky RA, Johns DR, Beal MF, Standaert DG, Simon DK. Somatic mitochondrial DNA mutations in single neurons and glia. Neurobiol Aging 2005; 26:1343-55. PubMed
  • Lin MT, Simon DK. No evidence for heritability of Parkinson disease in Swedish twins. Neurology 2005; 64:932; author reply 932. PubMed
  • Simon DK, Nishino S, Scammell TE. Mistaken diagnosis of psychogenic gait disorder in a man with status cataplecticus ("limp man syndrome"). Mov Disord 2004; 19:838-40. PubMed
  • Nichols WC, Uniacke SK, Pankratz N, Reed T, Simon DK, Halter C, Rudolph A, Shults CW, Conneally PM, Foroud T,. Evaluation of the role of Nurr1 in a large sample of familial Parkinson's disease. Mov Disord 2004; 19:649-55. PubMed
  • Tarnopolsky MA, Simon DK, Roy BD, Chorneyko K, Lowther SA, Johns DR, Sandhu JK, Li Y, Sikorska M. Attenuation of free radical production and paracrystalline inclusions by creatine supplementation in a patient with a novel cytochrome b mutation. Muscle Nerve 2004; 29:537-47. PubMed
  • Tarnopolsky MA, Bourgeois JM, Fu MH, Kataeva G, Shah J, Simon DK, Mahoney D, Johns D, MacKay N, Robinson BH. Novel SCO2 mutation (G1521A) presenting as a spinal muscular atrophy type I phenotype. Am J Med Genet A 2004; 125:310-4. PubMed
  • Simon DK, Lin MT, Zheng L, Liu GJ, Ahn CH, Kim LM, Mauck WM, Twu F, Beal MF, Johns DR. Somatic mitochondrial DNA mutations in cortex and substantia nigra in aging and Parkinson's disease. Neurobiol Aging 2003; 25:71-81. PubMed
  • Simon DK, Friedman J, Breakefield XO, Jankovic J, Brin MF, Provias J, Bressman SB, Charness ME, Tarsy D, Johns DR, Tarnopolsky MA. A heteroplasmic mitochondrial complex I gene mutation in adult-onset dystonia. Neurogenetics 2003; 4:199-205. PubMed
  • Zheng K, Heydari B, Simon DK. A common NURR1 polymorphism associated with Parkinson disease and diffuse Lewy body disease. Arch Neurol 2003; 60:722-5. PubMed
  • Simon DK, Lin MT, Pascual-Leone A. "Nature versus nurture" and incompletely penetrant mutations. J Neurol Neurosurg Psychiatry 2002; 72:686-9. PubMed
  • Anschel DJ, Simon DK, Llinas R, Joseph JT. Spongiform encephalopathy mimicking corticobasal degeneration. Mov Disord 2002; 17:606-7. PubMed
  • Lin MT, Simon DK, Ahn CH, Kim LM, Beal MF. High aggregate burden of somatic mtDNA point mutations in aging and Alzheimer's disease brain. Hum Mol Genet 2002; 11:133-45. PubMed
  • Simon DK, Lin MT, Ahn CH, Liu GJ, Gibson GE, Beal MF, Johns DR. Low mutational burden of individual acquired mitochondrial DNA mutations in brain. Genomics 2001; 73:113-6. PubMed
  • Simon DK, Tarnopolsky MA, Greenamyre JT, Johns DR. A frameshift mitochondrial complex I gene mutation in a patient with dystonia and cataracts: is the mutation pathogenic? J Med Genet 2001; 38:58-61. PubMed
  • Tabamo RE, Fernandez HH, Friedman JH, Simon DK. Young-onset Parkinson's disease: a clinical pathologic description of two siblings. Mov Disord 2000; 15:744-6. PubMed
  • Simon DK, Mayeux R, Marder K, Kowall NW, Beal MF, Johns DR. Mitochondrial DNA mutations in complex I and tRNA genes in Parkinson's disease. Neurology 2000; 54:703-9. 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, Pulst SM, Sutton JP, Browne SE, Beal MF, Johns DR. Familial multisystem degeneration with parkinsonism associated with the 11778 mitochondrial DNA mutation. Neurology 1999; 53:1787-93. PubMed
  • Simon DK. Parkinson disease in twins. JAMA 1999; 282:1328; author reply 1328-9. PubMed
  • Simon DK, Standaert DG. Neuroprotective therapies. Med Clin North Am 1999; 83:509-23, viii. PubMed
  • Simon DK, Johns DR. Mitochondrial disorders: clinical and genetic features. Annu Rev Med 1999; 50:111-27. PubMed
  • Simon DK, Rodriguez ML, Frosch MP, Quackenbush EJ, Feske SK, Natowicz MR. A unique familial leukodystrophy with adult onset dementia and abnormal glycolipid storage: a new lysosomal disease? J Neurol Neurosurg Psychiatry 1998; 65:251-4. PubMed
  • Simon DK, Roskies AL, O'Leary DD. Plasticity in the development of topographic order in the mammalian retinocollicular projection. Dev Biol 1994; 162:384-93. PubMed
  • Simon DK, Prusky GT, O'Leary DD, Constantine-Paton M. N-methyl-D-aspartate receptor antagonists disrupt the formation of a mammalian neural map. Proc Natl Acad Sci U S A 1992; 89:10593-7. PubMed
  • Simon DK, O'Leary DD. Responses of retinal axons in vivo and in vitro to position-encoding molecules in the embryonic superior colliculus. Neuron 1992; 9:977-89. PubMed
  • Simon DK, O'Leary DD. Influence of position along the medial-lateral axis of the superior colliculus on the topographic targeting and survival of retinal axons. Brain Res Dev Brain Res 1992; 69:167-72. PubMed
  • Simon DK, O'Leary DD. Development of topographic order in the mammalian retinocollicular projection. J Neurosci 1992; 12:1212-32. PubMed
  • Simon DK, O'Leary DD. Relationship of retinotopic ordering of axons in the optic pathway to the formation of visual maps in central targets. J Comp Neurol 1991; 307:393-404. PubMed
  • Simon DK, O'Leary DD. Limited topographic specificity in the targeting and branching of mammalian retinal axons. Dev Biol 1990; 137:125-34. PubMed
  • Shapiro ML, Simon DK, Olton DS, Gage FH, Nilsson O, Björklund A. Intrahippocampal grafts of fetal basal forebrain tissue alter place fields in the hippocampus of rats with fimbria-fornix lesions. Neuroscience 1988; 32:1-18. PubMed
  • Kleitman N, Simon DK, Schachner M, Bunge RP. Growth of embryonic retinal neurites elicited by contact with Schwann cell surfaces is blocked by antibodies to L1. Exp Neurol 1988; 102:298-306. PubMed
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