Anna Szekely, MD
Assistant Professor, Academic Clinician TrackCards
Appointments
Additional Titles
Attending Physician, Neurogenetics Program
Member, Program in Neurodevelopment and Regeneration
Contact Info
Appointments
Additional Titles
Attending Physician, Neurogenetics Program
Member, Program in Neurodevelopment and Regeneration
Contact Info
Appointments
Additional Titles
Attending Physician, Neurogenetics Program
Member, Program in Neurodevelopment and Regeneration
Contact Info
About
Titles
Assistant Professor, Academic Clinician Track
Attending Physician, Neurogenetics Program; Member, Program in Neurodevelopment and Regeneration
Appointments
Neurology
Assistant ProfessorPrimary
Other Departments & Organizations
Education & Training
- Research Fellowship
- Yale University School of Medicine (2000)
- Resident and Fellow
- Yale University School of Medicine (1999)
- Resident
- Yale University School of Medicine (1997)
- Internship
- Yale University School of Medicine (1994)
- MD
- Semmelweis University (1980)
Research
Overview
A deep commitment to academic medicine has fundamentally influenced my research interests, from years of basic molecular neuroscience research to becoming a double-boarded physician in Adult Neurology and Clinical Genetics with a continuing involvement in basic and translational research. My early studies focused on how conserved genetic programs can change in mature neurons in response to specific, transmitter-receptor mediated signals. The realization, that dynamic alteration of genetic programs may also play a fundamental role in pathological processes, led to my focus on how various layers of genomic architecture are influencing a phenotype in health and disease.
1. Exploitation of rare genetic disorders with Mendelian trait may provide novel insights into mechanisms of common disorders and complex biological processes, such as dementia, diabetes or aging, and recognized disease pathways can offer strategies for prevention, diagnosis, and therapy.
Among the simple Mendelian disorders of humans, Werner syndrome most closely resembles an acceleration of normal aging. In prior studies I demonstrated that WRN protein directly interacts with the DNA replication machinery. To define better cellular events that are specifically vulnerable to WRN deficiency, I used RNA interference (RNAi) to silence the expression of Wrn gene and other RecQ helicases, linked to different clinical phenotypes, in primary human fibroblasts. The series of investigations strongly suggest that defects in DNA repair of specific lesions produced by oxidative damage in slowly dividing or non-dividing cells account for those unique aspects of Werner syndrome that mimic normal aging. We also propose that over time these DNA lesions would also accumulate in stem/precursor cells impairing their replicative capacity, thereby contributing to the complex aging phenotype. Our observations attest to the concept that in metazoan models of aging most pathology occurs in organs made up of slowly dividing or non-dividing cells and that impaired DNA repair and genomic instability, driven by oxidative damage, may underlie normal human aging. These studies further fostered some of the current projects to understand the role of oxygen environment on stem cell pluripotency, stem cell aging and neural lineage specification.
2. Genetic mapping, identifying contributing gene mutations and variants, is only an initial step toward biological understanding of rare or common diseases. Creation of disease models, both in human cell culture and animals, is crucial. Human embryonic stem (hES) cells offer an unprecedented access to the earliest stage of development and modeling cell fate and function. In particular, molecular changes that arise during neuronal differentiation and fate specification can be elucidated that may offer key understanding of normal and abnormal human neural development and disease processes.
We are using a multifaceted approach with investigators of the Yale Stem Cell Center, integrating genomic, proteomic, and genetic experiments to elucidate the molecular events that control neural cell differentiation using hES cells as model system. We have analyzed global transcriptome changes that occur during the early differentiation of human embryonic stem cells (hESCs) into the neural lineage. Next generation, state-of-the-art sequencing analysis revealed a remarkable complexity in gene transcription and splicing dynamics during neural cell differentiation with a wealth of previously unannotated novel transcripts and spliced isoforms specific for each stage of differentiation. My current efforts are focused on a novel type of unbiased, genome-wide functional screen to identify genetic mechanisms that control the steps of the neural differentiation in hES cells. These studies and the platform would offer targets for more downstream goals, including mechanistic investigations or drug discovery.
Further, in a collaborative project within Yale, we investigate the effect of hypoxia in neural stem cell function to identify key genes and their networks that enable neuronal stem cells to repair the injured brain in mouse model of perinatal hypoxia and elucidate the role of these genes for human neuronal stem cell function. The project may provide clues how to promote neuronal stem cell regenerative potential in traumatic, vascular and degenerative disorders of the human brain.
3. To understand the genetic and molecular underpinnings of neurological and neurodevelopmental disorders, we capitalize on the recent technical development of reprogramming adult, differentiated somatic cells to pluripotent stem cells. These induced pluripotent stem (iPS) cells can be derived with a specific genetic and disease background and can differentiate into essentially any cell types of the body. Thus, by using patient-specific cells one may gain knowledge of key molecular players and abnormalities of neural fate determination and function to understand monogenic or complex developmental and degenerative brain disorders. This would not be otherwise possible to do in living CNS.
With other Yale investigators with interest in neurogenetics, we have recently launched the Program in Neurodevelopment and Regeneration and began to generate iPS cell lines derived directly from patients with various neurodevelopmental disorders with notable genetic component, such as autism spectrum disorders (ASD). We are particularly interested to understand if macrocephaly, a well replicated phenotype in ASD, may be related to intrinsic alterations neuronal stem cell properties governing cell proliferation and/or neural and glial differentiation and how these processes align with the patient-specific genomic architecture. Advanced technologies are used to reprogram skin cells, obtain data on patient-specific DNA variations and integrate with quantitative gene expression information and correlative epigenetic regulatory marks along with phenotypic analysis of neural differentiation. These projects may provide an exceptional chance to understand the genetic and cellular mechanisms underlying this complex disorder and also to correlate with the clinical phenotype. As a model in general, iPS cells provide an invaluable resource for in vitro disease modeling, pharmaceutical screening (drugs/small molecules) and potential for cell-replacement therapy.
4. Having the opportunity to clinically evaluate patients with rare neurogenetic conditions, I interact regularly with scientists of the field to pursue molecular studies. I am particularly interested to contribute to the ongoing gene discovery efforts at Yale for autism, mental retardation and disorders of brain malformations, among others.
- Integrated approach to neural differentiation of human embryonic stem (hES) cells - use the latest advances in large-scale genomic and proteomic approaches to decipher critical elements of neuronal differentiation from human embryonic stem (ES) cells. Genes and pathways identified by these studies provide a basis for mechanistic investigations, construction of model biological networks and drug discovery.
- Cellular and genetic determinants of increased head size in autism - novel genetic, genomic and morphological approaches are used in this collaborative project to study neuronal differentiation of induced pluripotent stem (iPS) cells derived from patients with autism spectrum disorder. The project provides an unprecedented chance to understand the biological mechanisms of this disease.
- Effect of hypoxia on neural stem cell function in mouse and human - this collaborative project aims to identify key genes and their networks that enable neuronal stem cells to repair the injured brain in mouse model of perinatal hypoxia and elucidate their role for human neuronal stem cell function. The project may uncover how to promote neuronal stem cell regenerative potential in traumatic, vascular and degenerative disorders of the human brain.
Medical Subject Headings (MeSH)
Research at a Glance
Yale Co-Authors
Publications Timeline
Research Interests
Flora Vaccarino, MD
Jessica Mariani, PhD
Livia Tomasini
Alexej Abyzov, PhD
Alexandre Jourdon, PhD
Angeli Landeros-Weisenberger, MD
Neurogenesis
Genetic Variation
Gene Silencing
Publications
2023
Author Correction: Modeling idiopathic autism in forebrain organoids reveals an imbalance of excitatory cortical neuron subtypes during early neurogenesis
Jourdon A, Wu F, Mariani J, Capauto D, Norton S, Tomasini L, Amiri A, Suvakov M, Schreiner J, Jang Y, Panda A, Nguyen C, Cummings E, Han G, Powell K, Szekely A, McPartland J, Pelphrey K, Chawarska K, Ventola P, Abyzov A, Vaccarino F. Author Correction: Modeling idiopathic autism in forebrain organoids reveals an imbalance of excitatory cortical neuron subtypes during early neurogenesis. Nature Neuroscience 2023, 26: 2035-2035. PMID: 37674007, DOI: 10.1038/s41593-023-01447-9.Peer-Reviewed Original ResearchCitationsAltmetricModeling idiopathic autism in forebrain organoids reveals an imbalance of excitatory cortical neuron subtypes during early neurogenesis
Jourdon A, Wu F, Mariani J, Capauto D, Norton S, Tomasini L, Amiri A, Suvakov M, Schreiner J, Jang Y, Panda A, Nguyen C, Cummings E, Han G, Powell K, Szekely A, McPartland J, Pelphrey K, Chawarska K, Ventola P, Abyzov A, Vaccarino F. Modeling idiopathic autism in forebrain organoids reveals an imbalance of excitatory cortical neuron subtypes during early neurogenesis. Nature Neuroscience 2023, 26: 1505-1515. PMID: 37563294, PMCID: PMC10573709, DOI: 10.1038/s41593-023-01399-0.Peer-Reviewed Original ResearchCitationsAltmetricMeSH Keywords and ConceptsConceptsIdiopathic autism spectrum disorderCortical neuron subtypesAutism spectrum disorderEarly cortical developmentCortical organoidsCortical plateExcitatory neuronsCortical developmentRare formNeuron subtypesUnaffected fatherASD pathogenesisForebrain organoidsEarly neurogenesisRare variantsIdiopathic autismRisk genesTranscriptomic alterationsNeuronsProbandsSingle-cell transcriptomicsForebrain developmentSpectrum disorderTranscriptomic changesAlterationsEfficient reconstruction of cell lineage trees for cell ancestry and cancer
Jang Y, Fasching L, Bae T, Tomasini L, Schreiner J, Szekely A, Fernandez T, Leckman J, Vaccarino F, Abyzov A. Efficient reconstruction of cell lineage trees for cell ancestry and cancer. Nucleic Acids Research 2023, 51: e57-e57. PMID: 37026484, PMCID: PMC10250207, DOI: 10.1093/nar/gkad254.Peer-Reviewed Original ResearchCitationsAltmetricMeSH Keywords and ConceptsConceptsLineage treesCell ancestryCell lineage treesFirst cell divisionStem cell linesPluripotent stem cell lineLineage reconstructionInduced pluripotent stem cell lineCell divisionCancer progressionLineage representationCell linesMosaic mutationsHuman skin fibroblastsTreesMutationsAncestrySkin fibroblastsMultiple cellsGenomeLineagesZygotesLinesFibroblastsCells
2022
Characterization of human basal ganglia organoids
Brady M, Mariani J, Koca Y, Szekely A, King R, Bloch M, Landeros-Weisenberger A, Leckman J, Vaccarino F. Characterization of human basal ganglia organoids. Molecular Psychiatry 2022, 27: 4823-4823. PMID: 36536052, DOI: 10.1038/s41380-022-01914-y.Peer-Reviewed Original ResearchAltmetricMeSH KeywordsMispatterning and interneuron deficit in Tourette Syndrome basal ganglia organoids
Brady M, Mariani J, Koca Y, Szekely A, King R, Bloch M, Landeros-Weisenberger A, Leckman J, Vaccarino F. Mispatterning and interneuron deficit in Tourette Syndrome basal ganglia organoids. Molecular Psychiatry 2022, 27: 5007-5019. PMID: 36447010, PMCID: PMC9949887, DOI: 10.1038/s41380-022-01880-5.Peer-Reviewed Original ResearchCitationsAltmetricMeSH Keywords and ConceptsConceptsTourette syndromeInterneuron deficitsGABAergic interneuronsHealthy controlsNeurodevelopmental underpinningsNeuropathological deficitsBG circuitryNeuropsychiatric disordersDecreased differentiationT patientsInterneuronsAltered expressionPotential mechanismsCilia disruptionSonic hedgehogOrganoidsStem cellsTS individualsPluripotent stem cellsGli transcription factorsDeficitsOrganoid differentiationEarly stagesCholinergicPatients
2021
Miglustat Therapy for SCARB2-Associated Action Myoclonus–Renal Failure Syndrome
Quraishi IH, Szekely AM, Shirali AC, Mistry PK, Hirsch LJ. Miglustat Therapy for SCARB2-Associated Action Myoclonus–Renal Failure Syndrome. Neurology Genetics 2021, 7: e614. PMID: 34337151, PMCID: PMC8320328, DOI: 10.1212/nxg.0000000000000614.Peer-Reviewed Original ResearchCitationsAltmetricConceptsAction myoclonus-renal failure syndromeNeurologic symptomsAction myoclonusFailure syndromeProgressive myoclonic epilepsySubstrate reduction therapyWhole-exome sequencingMiglustat therapyAvailable medicationsEarly mortalityReduction therapyMyoclonic epilepsySteady worseningGaucher diseaseMyoclonusGlycosphingolipid metabolismExome sequencingGene mutationsGlucosylceramide accumulationPatientsSeizuresMiglustatSyndromeTherapySymptomsEarly developmental asymmetries in cell lineage trees in living individuals
Fasching L, Jang Y, Tomasi S, Schreiner J, Tomasini L, Brady MV, Bae T, Sarangi V, Vasmatzis N, Wang Y, Szekely A, Fernandez TV, Leckman JF, Abyzov A, Vaccarino FM. Early developmental asymmetries in cell lineage trees in living individuals. Science 2021, 371: 1245-1248. PMID: 33737484, PMCID: PMC8324008, DOI: 10.1126/science.abe0981.Peer-Reviewed Original ResearchCitationsAltmetric
2020
Ring chromosome formation by intra‐strand repairing of subtelomeric double stand breaks and clinico‐cytogenomic correlations for ring chromosome 9
Chai H, Ji W, Wen J, DiAdamo A, Grommisch B, Hu Q, Szekely AM, Li P. Ring chromosome formation by intra‐strand repairing of subtelomeric double stand breaks and clinico‐cytogenomic correlations for ring chromosome 9. American Journal Of Medical Genetics Part A 2020, 182: 3023-3028. PMID: 32978894, DOI: 10.1002/ajmg.a.61890.Peer-Reviewed Original ResearchCitations
2018
Hereditary spastic paraplegia presenting as limb dystonia with a rare SPG7 mutation.
Schaefer SM, Szekely AM, Moeller JJ, Tinaz S. Hereditary spastic paraplegia presenting as limb dystonia with a rare SPG7 mutation. Neurology Clinical Practice 2018, 8: e49-e50. PMID: 30588391, PMCID: PMC6294529, DOI: 10.1212/cpj.0000000000000552.Peer-Reviewed Original ResearchCitations
2016
Effective Treatment of Paroxysmal Nonkinesigenic Dyskinesia With Oxcarbazepine
Kumar A, Szekely A, Jabbari B. Effective Treatment of Paroxysmal Nonkinesigenic Dyskinesia With Oxcarbazepine. Clinical Neuropharmacology 2016, 39: 201-205. PMID: 27046658, DOI: 10.1097/wnf.0000000000000149.Peer-Reviewed Original ResearchCitationsAltmetricMeSH Keywords and ConceptsConceptsParoxysmal nonkinesigenic dyskinesiaRare chronic disorderOutcome of treatmentSeverity of episodesAvailable therapiesChronic disordersClinical trialsInvoluntary movementsEffective treatmentOxcarbazepinePharmaceutical agentsDyskinesiaPatientsTreatmentDisordersTherapyDebilitatingDiseaseTrialsSeverity
Academic Achievements and Community Involvement
activity European Journal of Paediatric Neurology
Peer Review Groups and Grant Study SectionsReviewerDetailsad hoc manuscript reviewer2007 - Presentactivity Deutsche Forschungsgemeinschaft (German Research Foundation)
Peer Review Groups and Grant Study SectionsReviewerDetailsad hoc grant reviewer06/01/2013 - Presentactivity Yale University
Professional OrganizationsModeratorDetailsNeuroscience Clinical Skills Tutorial for Medical Students2004 - Presentactivity Yale University
Professional OrganizationsMemberDetailsProgram in Neurodevelopment and Regeneration2009 - Presentactivity Yale University
Professional OrganizationsMentorDetails“Science, Technology and Research Scholars” (STARS) Program for Undergraduate Students2003 - 2007
Clinical Care
Overview
Clinical Specialties
Fact Sheets
Neurogenetics
Learn More on Yale MedicinePsychological Assessment of Children
Learn More on Yale MedicineChild Development
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Board Certifications
Clinical Genetics and Genomics
- Certification Organization
- AB of Medical Genetics and Genomics
- Latest Certification Date
- 2018
- Original Certification Date
- 2007
Neurology
- Certification Organization
- AB of Psychiatry & Neurology
- Latest Certification Date
- 2016
- Original Certification Date
- 2005
Yale Medicine News
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View this doctor's clinical profile on the Yale Medicine website for information about the services we offer and making an appointment.
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News
- August 11, 2021
Discoveries & Impact (August 2021)
- July 20, 2015
Making ‘miniature brains’ from skin cells to better understand autism
- February 28, 2013
Stem cells reveal a long-hidden mosaic
- November 18, 2012
Skin cells reveal DNA’s genetic mosaic
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The Anlyan Center
Lab
300 Cedar Street, Ste S320
New Haven, CT 06519
The Anlyan Center
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300 Cedar Street, Ste S320
New Haven, CT 06519
Appointments
203.737.2278Patient Care Locations
Are You a Patient? View this doctor's clinical profile on the Yale Medicine website for information about the services we offer and making an appointment.