Dr. David K Simon
Dr. David K Simon
POSITION TITLE: Professor of Neurology, Beth Israel Deaconess Med Ctr & Harvard Medical School
EDUCATION/TRAINING
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INSTITUTION AND LOCATION |
DEGREE (if applicable) |
Completion Date MM/YYYY |
FIELD OF STUDY |
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Johns Hopkins University, Baltimore, MD |
B.A. |
05/1986 |
Biology |
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Washington U. School of Medicine, St. Louis, MO |
M.D.,Ph.D. |
05/1993 |
Medicine, Neuroscience |
Dr. Simon completed neurology residency training at Harvard in 1997, and a movement disorders fellowship at MGH in 1997-8. Since then, his lab studies mitochondrial dysfunction and neurodegeneration, with a focus on aging and age-related neurodegenerative diseases including Alzheimer’s disease (AD) and Parkinson’s disease (PD), with a particular interest in potential neuroprotective strategies. Dr. Simon has extensive experience in studying mitochondrial dysfunction and somatic mitochondrial DNA (mtDNA) mutations in the brain during aging and in age-related neurodegenerative diseases. His lab conducts behavioral, biochemical, histological, and molecular biological investigations in cellular and mouse models of aging and PD. This includes studies of PGC-1α, a master regulator of mitochondrial biogenesis and antioxidant activities, as a neuroprotective target. The lab is now studying regulatory pathways for PGC-1α in cellular and mouse models of AD and PD. He also conducts translational studies of novel potential neuroprotective targets, including USP30, which regulates mitophagy, and VSP35, a component of the retromer complex that regulates alpha-synyuclein degradation pathways. Dr. Simon served on the Steering Committees for multicenter clinical studies in PD patients, including the FS-ZONE study of pioglitazone, the NILO-PD study of nilotinib and the SPARK study of monoclonal antibodies against alpha-synuclein. He also headed a biomarker substudy of the FS-ZONE study. He served as Chair of the Scientific Review Committee of the Parkinson Study Group (PSG), Chair of the PSG Genetics and Environmental Working Group, and was an elected member of the PSG Executive Committee. He completed a 4-year term as a member of the NIH Molecular Neurogenetics study section and has served since 2012 on the NINDS Biospecimen Review Access Committee (PD-BRAC). He is Chair of the Cure Parkinson’s Trust’s international Linked Clinical Trials Committee and Chair of the Scientific Advisory Board of the Weston Brain Institute.
Ongoing and recently completed projects include:
NINDS R01NS133187 (Multi-PI: Simon; Wei) 4/1/24 – 3/31/29
“Targeting the FBXW7/PGC1 Pathway as a Therapeutic Strategy for Parkinson's Disease”
Studies to investigate a novel PGC-1alpha regulatory pathway as a target for neuroprotection in Parkinson’s disease.
NINDS R21 NS130095 (Simon) 9/1/23 – 8/31/25
“USP30 Inhibition as a Therapeutic Strategy in Parkinson's Disease”
Translational studies of a small molecule USP30 inhibitor as a potential neuroprotective agent in an alpha-synuclein based mouse model of Parkinson’s disease
Weston Brain Institute Advisor Award (Simon) 4/1/16 - ongoing
Grant to support a postdoctoral fellow to study the role of VPS35 as a therapeutic target for neuroprotection in an alpha-synculein mouse model of Parkinson’s disease.
Citations:
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St-Pierre J, Drori S, Uldry M, Silvaggi JM, Rhee J, Jäger S, Handschin C, Zheng K, Lin J, Yang W, Simon DK, Bachoo R, Spiegelman BM. Suppression of reactive oxygen species and neurodegeneration by the PGC-1 transcriptional coactivators. Cell. 2006;127(2):397-408 (cited >2,500 times)
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Clark J, Silvaggi J, Kiselak T, Zheng K, Clore EL, Dai Y, Bass C, Simon DK. Overexpression of Pgc-1a increases susceptibility to MPTP and promotes dopamine depletion associated with decreased Pitx3. PLOS ONE; 2012;7(11):e48925. PMCID:PMC3492133.
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Zhang Fang T-S, Sun Y, Pearce AC, Eleuteri SC, Kemp M, Luckhurst CA, Williams R, Mills R, Almond S, Burzynski L, Markus N, Lelliott CJ, Karp NA, Adams DJ, Jackson SP, Zhao J-F, Ganley I, Thompson PW, Balmus G, Simon DK. Knockout or inhibition of USP30 protects dopaminergic neurons in a Parkinson’s disease mouse model. Nature Communications; 2023;14,7295; PMCID: PMC10643470.
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Eleuteri S, Wang B, Cutillo G, Zhang Fang TS, Tao K, Qu Y, Yang Q, Wei W, Simon DK. PGC-1α regulation by FBXW7 through a novel mechanism linking chaperone-mediated autophagy and the Ubiquitin-proteasome system. FEBS; In Press
Positions and Honors
Graduate and Post-graduate Training:
1997 – 1998 Clinical and Research Fellow in Movement Disorders, Dept of Neurology, MGH, Boston, MA
1994 – 1997 Resident in Neurology, Harvard-Longwood Neurology Training Program, Boston, MA
1993 – 1994 Intern in Medicine, Jewish Hospital, St. Louis
1988 – 1992 Ph.D., Dissertation Research, Neural Sciences, Washington U Schl Med, St. Louis, MO
Academic and Hospital Appointments:
2016 – Professor, Neurology, Harvard Medical School, Boston
2015 – Chief, Division of Movement Disorders at BIDMC
2015 – Medical Director, National Parkinson Foundation Center of Excellence at BIDMC
2008 – 2016 Associate Professor, Neurology, Harvard Medical School, Boston
2005 – 2014 Assistant Medical Director; National Parkinson Foundation Center of Excellence at BIDMC
2000 – 2008 Assistant Professor, Neurology, Harvard Medical School, Boston
1998-current Staff Neurologist, Beth Israel Deaconess Medical Center, Boston
1998 – 2000 Instructor in Neurology, Harvard Medical School, Boston
Specialty Board Certification:
1998-current Neurology (American Board of Psychology and Neurology)
Awards and Other Professional Activities
2025 – Chair, NINDS Parkinson’s Disease Biospecimen Review Access Committee (PD-BRAC)
2024 – Board of Clinical Advisors member, Neuropacs; automated imaging diagnostics company
2023 – Michael J Fox Foundation Parkinson's Disease Research Exchange (PDRx) member
2023 – Global Steering Committee Member; “ACTIVATE” study (GCase activator in PD); Bial
2022 – Chair, Cure Parkinson Trust International Linked Clinical Trials Committee (iLCT)
2021 – Global Parkinson’s Genetics Program (GP2) collaborator (NET-PD cohort)
2021 – Senior Advisor – Clinical Research; Bial Biotech
2020 – 2023 Member, Advisory Council, Parkinson’s Foundation PCORI palliative care project
2020 – Cure Parkinson Trust International Linked Clinical Trials Advisory Subcommittee member for the Australian Parkinson’s Mission (APM).
2020 Co-Chair Parkinson Study Group Nominating Committee
2019 Plenary speaker, IAPRD World Congress, Montreal, Canada
2017 – 2022 Steering Committee member, Biogen-sponsored study of anti-synuclein antibody therapy in PD
2017 – 2021 Steering Committee member, MJFF-sponsored phase 2 clinical study of Nilotinib in PD
2017 – 2019 Elected member, Parkinson Study Group (PSG) Executive Committee (3 year term)
2016 Plenary speaker, Movement Disorders Society International Congress, Berlin, Germany
2016 Chair, Parkinson Study Group “Genetics and Environmental Risk Factors” Working Group
2015 – Castle Connolly “Top Doctor” 2014, ’15, ‘16, ‘17, ‘18, ‘19, ’20, ’21, ’22, ‘23
2015 – Cure Parkinson Trust International Linked Clinical Trials Committee member (iLCT)
2015 – W. Garfield Weston Foundation: Weston Brain Institute, Toronto, Canada: Scientific Advisory Board Member; Chair of the Scientific Advisory Board since 2018.
2014 – NINDS Parkinson’s Disease Biospecimen Review Access Committee (PD-BRAC) member
2014 – 2017 Editorial Board Member; Annals of Neurology
2014 Michael J Fox Foundation Biomarker Workshop moderator
2013 – 2015 Chair, Parkinson Study Group (PSG) Scientific Review Committee (co-Chair 2011 – 2013)
2013 – 2015 Parkinson Study Group (PSG) Executive Committee member (as SRC Chair)
2013 NIH (NINDS) Workshop on Alz Dis & Related Dis; DLB Genetics: Lead Discussant
2012 – 2014 Parkinson Study Group representative to grant review committee for the Michael J. Fox Foundation RFA for Utilizing DATATOP and other Biospecimens
2010 – 2015 Co-Chair, Parkinson Study Group “Genetics and Environmental Risk Factors” Working Group
2010 Lead Guest Editor, special issue for “Parkinson’s Disease”: Mitochondria and PD
2009 – 2015 Steering Committee member, “FS-Zone” multicenter clinical study of pioglitazone in PD
2009 – 2015 Parkinson Study Group (PSG) Scientific Review Committee (SRC) member
2009 – 2013 NIH Molecular Neurogenetics (MNG) study section Member (4-year term)
2008 – National Scientific Advisory Committee, AFAR (American Federation for Aging Research)
2006 – 2009 NIH Study Sections: Ad Hoc Reviewer: NSD-A (2006) MNG (Oct 2008; Feb and June 2009); RDCRC/ZRG1 Hop-Y 50 (2009); ZRG1 ETTN-G [95] S (2009); ZRG1 PSE-J [58] R (2009).
2006 – 2008 National Parkinson Foundation “Mega-Research Project” Award (Co-Investigator)
2005 – Multiple Michael J Fox Foundation Grant and Progress Review Committees
2005 Pfizer/AFAR Innovations in Aging Research Award
2002 – Member, Harvard NeuroDiscovery Center
2001 – 2004 George C. Cotzias Fellowship Award from the American Parkinson Disease Association
1999 – Member, Parkinson Study Group (PSG)
1993 Irwin Levy Prize in Neurology and Neurological Surgery
1992 Spencer T. and Ann W. Olin Medical Scientist Fellowship Award
1985 Phi Beta Kappa and Alpha Epsilon Delta Honors Societies (Johns Hopkins University)
Multicenter Clinical Trials (PI or site PI role):
2021 – WAID: Web-based Automated Imaging Differentiation in Parkinsonism; PI at BIDMC
2021 – PD GENEration: Parkinson’s Foundation PD genetic testing project; PI at BIDMC
2021 – “TOPAZ” study of zoledronic acid to prevent fractures from falls in PD; PI at BIDMC
2019 - 2023 Site PI for “PRISM” study of NLY01 as a potential disease-modifying therapy for PD (Neuraly)
2019 - 2021 Co-Invest. at BIDMC: “AADC in Advanced PD Trial – ADAPT)”, a multicenter double-blind sham-surgery controlled gene therapy study for advanced Parkinson’s disease; Voyager Therapeutics.
2016 – 2019 SURE-PD3 NINDS-supported phase 3 multicenter clinical study of inosine to raise uric acid as a potential disease-modifying therapy in PD; PI at BIDMC.
2015 – 2018 Lysosomal Therapeutics: Clinical biomarker and target engagement study of a potential neuroprotective agent targeting the glucocerebrosidase pathway in Parkinson’s disease.
2015 – 2019 BioElectron Technology phase 2 clinical study of a mitochondria-based potential neuroprotective agent in Parkinson’s disease; PI at BIDMC
2009 – 2015 “FS-Zone” multicenter clinical study of pioglitazone in Parkinson’s disease (Site Investigator; Steering Committee member; PI of biomarker substudy funded by the Michael J Fox Found.)
2007 - 2014 “Effects of Coenzyme Q10 in PSP…:” (multicenter double-blind study); PI at BIDMC
2006 – 2011 “QE3” multicenter study of CoQ10 as a potential neuroprotective therapy for PD; PI at BIDMC
2006 – 2009 Overall PI: 2-site study (with Dr. Stanley Fahn at Columbia U) of the efficacy of visual cues for freezing of gait in Parkinson’s disease. Supported by the National Parkinson Foundation
2004 – 2009 DNA Repository for Parkinson’s Disease. Head of a multicenter effort to collect data and DNA samples for the NINDS Repository at Coriell in conjunction with the NET-PD studies
2002 – 2015 Neuroprotection in Parkinson’s Disease; “NET-PD” (U10 NS44482; NINDS): PI at BIDMC. Clinical trials of potential neuroprotective agents in PD: FS-1, FS-TOO, and LS1 studies
1999 – 2009 Riluzole in Parkinson’s disease: Clinical neuroprotection study (Aventis). PI at BIDMC
1998 – 2009 PROGENI: Genome wide screen in PD sib pair (NINDS / Parkinson Study Group); PI at BIDMC
Contributions to Science (with selected references)
1. Somatic mtDNA mutations increase with age and reach high levels at early pathological stages in substantia nigra neurons in PD:
The cause of mitochondrial dysfunction in Parkinson’s disease (PD) is a critical question in the field. Indirect evidence has implicated mitochondrial DNA (mtDNA) mutations. We found that somatic mtDNA mutations accumulate with age in the brain, but initially we found no difference in levels in brain homogenate from late-stage PD patients compared to controls. We next used laser capture microdissection to examine mutation levels specifically in substantia nigra neurons, and also examined very early pathological stages of PD. Somatic mtDNA mutation levels were significantly higher in neurons than in glia. Importantly, we found a remarkable and significant elevation of mtDNA point mutation levels in substantia nigra neurons early PD but not in those few neurons that survive to late stages of PD. Our data, culminating in this 2012 Annals of Neurology paper, represent the strongest evidence to date implicating somatic mtDNA mutations in mitochondrial dysfunction and neurodegeneration in PD.
a. 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(3):703-9.
b. Simon DK, Lin MT, Zheng L, Liu GJ, Ahn CH, et al. Somatic mitochondrial DNA mutations in cortex and substantia nigra in aging and Parkinson's disease. Neurobiol Aging. 2004;25(1):71-81.
c. 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(10):1343-55.
d. Lin MT, Cantuti-Castelvetri I, Zheng K, Jackson KE, Tan YB, Arzberger T, Lees AJ, Betensky RA, Beal MF, Simon DK. Somatic mtDNA mutations in early Parkinson’s and incidental Lewy body disease. Ann Neurol 2012;71:850-4. PMCID:PMC3383820
2. Somatic mtDNA mutations at levels similar to those found in some SN neurons in early PD can be functionally significant. Enhancing mitophagy through mTOR inhibition promotes their elimination: The studies outlined above in postmortem human tissues are limited in that they can’t address causality. Therefore, we moved to cellular and mouse models. The POLG “mutator” mice express a mutant mtDNA polymerase leading to an accelerated accumulation of somatic mtDNA mutations. These mice develop mitochondrial dysfunction, behavioral deficits and features of premature aging. We also have found loss of striatal dopaminergic terminals in the POLG mice, which occurs at levels of mutations that we found to be present in some SN neurons in PD. These studies further implicate a role for the accumulation of somatic mtDNA mtuations in neurodegeneration in PD. We also published a novel metabolomics study implicating PARP activation in the brain as a potential mechanism contributing to the phenotype in POLG mutator mice. We also have demonstrated in vitro the ability to drive down levels of heteroplasmic mtDNA mutations by enhancing mitophagy through mTOR inhibition.
a. 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. Human Mol Genet; 2014;23:637-47. PMCID: PMC3888257
b. 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. Neurotoxicology and Teratology; 2014 Nov-Dec;46:62-7; PMCID:PMC4293310.
c. Clark-Matott J, Saleem A, Dai Y, Ma X, Safdar A, Tarnopolsky M, Simon DK. Metabolomic Analysis of Exercise Effects in the POLG Mitochondrial DNA Mutator Mouse Brain. Neurobiol Aging; 2015 Nov;36(11):2972-83. PMCID: PMC4609600.
d. Simon DK, Matott JC, Espinosa J, Abraham NA. Mitochondria DNA Mutations in Parkinson’s Disease Brain. Acta Neuropath Comm; 2017;5:33; PMCID: PMC5410101.
3. Deficiency of PGC-1alpha, a molecule that regulates mitochondrial function and antioxidant defenses, may play a key role in PD, and thus enhancing PGC-1alpha activity is a promising neuroprotective strategy:
We collaborated with Dr. Bruce Spiegelman on the first paper that raised the possibility of a role for PGC-1ɑ by showing enhanced vulnerability to MPTP in PGC-1α deficient mice. My lab’s role in this 2006 Cell publication (cited over 2,500 times) was to show for the first time that upregulation of PGC-1α in cell lines is protective. Subsequently others found that PGC-1α activity is low in substantia nigra neurons at very early stages of PD, and PGC-1α deficiency was linked to 2 genetic causes of PD (α-synuclein toxicity and loss of Parkin). We subsequently were the first to demonstrate an association of common variants in the PGC-1α gene with the risk and age of onset of PD, as well as with longevity. Together, these data have led to great interest in upregulation of PGC-1α as a neuroprotective strategy. We conducted an initial translational study using a viral vector to upregulate PGC-1α in the substantia nigra in mice. We found unexpectedly that very high levels of PGC-1α cause dopamine depletion, potentially through suppression of Pitx3, leading to specific predictions regarding how to safely harness the neuroprotective potential of PGC-1α.
a. St-Pierre J, Drori S, Uldry M, Silvaggi JM, Rhee J, Jäger S, Handschin C, Zheng K, Lin J, Yang W, Simon DK, Bachoo R, Spiegelman BM. Suppression of reactive oxygen species and neurodegeneration by the PGC-1 transcriptional coactivators. Cell. 2006;127(2):397-408 (cited >2,500 times)
b. 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 May 19;12(1):69. PMCID: PMC3112073.
c. Clark J, Silvaggi J, Kiselak T, Zheng K, Clore EL, Dai Y, Bass C, Simon DK. Overexpression of Pgc-1a increases susceptibility to MPTP and promotes dopamine depletion associated with decreased Pitx3. PLOS ONE; 2012;7(11):e48925. PMCID:PMC3492133.
d. Eleuteri S, Wang B, Cutillo G, Zhang Fang TS, Tao K, Qu Y, Yang Q, Wei W, Simon DK. PGC-1α regulation by FBXW7 through a novel mechanism linking chaperone-mediated autophagy and the Ubiquitin-proteasome system. FEBS; 2025;292(2):332-354; DOI: 10.1111/febs.17276
4. Clinical and translational neuroprotection studies:
Dr. Simon has conducted multiple other clinical and laboratory investigations of potential neuroprotective strategies relating to mitochondrial dysfunction and oxidative stress in PD. In conjunction with a series of multicenter clinical neuroprotection studies, Dr. Simon led a substudy to examine the association of caffeine with rate of progression. This revealed an unexpected deleterious interaction of caffeine with creatine, with a faster rate of progression of PD associated with high caffeine intake among PD patients also taking creatine. Dr. Simon’s lab also demonstrated a protective effect of n-acetylcysteine (NAC)in α-synuclein overexpressing mice, and NAC now is moving forward in clinical trials in PD. Dr. Simon was the site PI for multiple clinical studies of PD, including phase 3 studies of CoQ10 and creatine as potential neuroprotective agents in PD. Dr. Simon also has served on steering committees to investigate potential disease-modifying treatments (pioglitazone; nilotinib; mAbs against alpha-synuclein) and led a biomarker substudy in conjunction with a phase 2 multicenter study of pioglitazone, which has antioxidant effects and also upregulates PGC-1α activity.
a. Clark J, Clore E, Zheng K, Sacchetti M, Masliah E, Simon DK. Oral n-acetylcysteine attenuates loss of dopaminergic terminals in α-synuclein overexpressing mice. PLoS ONE, 2010 Aug 23;5(8):e12333. PMCID: PMC2925900.
b. Lang AE, Siderowf AD, Macklin EA, Poewe W, Brooks DJ, Fernandez HH, Rascol O, Giladi N, Stocchi F, Tanner CM, Postuma RB, Simon DK, Tolosa E, Mollenhauer B, Cedarbaum JM, Fraser K, Xiao J, Evans KC, Graham DL, Sapir I, Inra J, Hutchinson RM, Yang M, Fox T, Haeberlein SB, Dam T, for the SPARK Investigators. Trial of Cinpanemab in Early Parkinson’s Disease. N Engl J Med, 2022;387:408-20. DOI: 10.1056/NEJMoa2203395.
c. Eleuteri S, Fang TSZ, Cutillo G, Persico M, Simon DK. Retromer stabilization using a pharmacological chaperone protects in an α-synuclein based mouse model of Parkinson’s. Res Sq 2023; Preprint; PMCID: PMC10602148.
d. Zhang Fang T-S, Sun Y, Pearce AC, Eleuteri SC, Kemp M, Luckhurst CA, Williams R, Mills R, Almond S, Burzynski L, Markus N, Lelliott CJ, Karp NA, Adams DJ, Jackson SP, Zhao J-F, Ganley I, Thompson PW, Balmus G, Simon DK. Knockout or inhibition of USP30 protects dopaminergic neurons in a Parkinson’s disease mouse model. Nature Communications; 2023;14,7295; DOI: 10.1038/s41467-023-42876-1
Complete List of Published Work in MyBibliography (google scholar h-index: 55) https://pubmed.ncbi.nlm.nih.gov/?term=simon+dk&sort=date
