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
  • 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
  • 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-1α overexpression downregulates Pitx3 and increases susceptibility to MPTP toxicity associated with decreased Bdnf. PLoS ONE 2012; 7:e48925. 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
  • Clark J, Dai Y, Simon DK. Do somatic mitochondrial DNA mutations contribute to Parkinson's disease? Parkinsons Dis 2011; 2011:659694. 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
  • 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
  • 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
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