Huntington disease pathogenic mechanisms

Sadri-Vakili Neuroepigenetics Laboratory

The laboratory focuses on identifying common mechanisms that cause neurodegenerative disease in order to identify novel therapeutic targets.

Lab Phone: 617-726-0332

Office Phone: 617-724-1487

MassGeneral Institute for Neurodegenerative Disease (MIND)



Dr. Sadri-Vakili directs the NeuroEpigenetics laboratory at the MassGeneral Institute for Neurodegenerative Disease, where she focuses on identifying common mechanisms that cause neurodegenerative disease in order to identify novel therapeutic targets. Thus far, the laboratory has identified disease specific alterations in multiple cellular pathways using human samples as well as cellular and animal models of ALS, HD, and X-linked dystonia Parkinsonism (XDP). In ALS, the laboratory is assessing the pathogenic role of neuroinflammation, oxidative stress, and the epigenome. Together with colleagues from the NCRI the Sadri-Vakili lab uses biofluids to identify new diagnostic and prognostic biomarkers of disease. In addition, Dr. Sadri-Vakili works closely with partners in industry and routinely tests the therapeutic effects of novel small molecules and FDA-approved compounds in animal models of ALS. Currently, the laboratory is assessing the neuroprotective efficacy of an anti-inflammatory FDA-approved compound in a mouse model of ALS with the hope of moving it forward to testing in people.

Huntington’s Disease

The Huntington’s disease projects are focused on the study of histone modifications, in particular histone acetylation.  Our previous findings have shown that alteration in histone acetylation is one mechanism that underlies transcriptional dysregulation in Huntington’s disease. Targeting histone modifying enzymes such as histone deacetylases is a novel approach for the treatment of several neurodegenerative disorders including Huntington’s disease. Currently, as a collaborative effort we are focused on identifying specific and novel histone deacetylase inhibitors for the treatment of Huntington’s disease. We apply the most current techniques, such as chromatin immunoprecipitation, real-time PCR, and genome-wide location analysis, and use both cell as well as animal models of Huntington’s disease for our studies.

pathenogenic mechanisms diagram

Investigating molecular

Molecular Mechanisms

The NeuroEpigenetics lab is also interested in investigating the molecular mechanisms that underlie drug abuse as part of several collaborations with colleagues from MGH, University of Pennsylvania, and Mclean Hospital. It is now clear that repeated intake of drugs of abuse alters gene expression in limbic nuclei that underlies the neuronal and behavioral plasticity that characterizes addiction. Our research is aimed at identifying the epigenetic marks involved in the regulation of cocaine-induced alterations in gene expression in limbic nuclei. More specifically work from our laboratory focuses on determining how cocaine-induced chromatin remodeling leads to alterations in brain-derived neurotrophic factor (BDNF) expression within the medial prefrontal cortex following exposure to cocaine.  Our most recent efforts are focused on determining whether these specific epigenetic marks are heritable and persist beyond the F1 generation in rodents exposed to cocaine prenatally or via self-administration.

Group Members

Ghazaleh Sadri-Vakili

Principal Investigator

Ghazaleh Sadri-Vakili, MS, PhD

  • Assistant Professor of Neurology,
    Harvard Medical School
  • Assistant in Neuroscience,
    Massachusetts General Hospital


Lab Members

  • Shayna B. Darnell, BA - Lab Technician
  • Megan Huizenga - Research Assistant 
  • Khampaseuth (Susan) Rasakham, PhD - Postdoctoral Fellow
  • Gavin R. Sangrey, BA - Lab Technician

Research Projects

Huntington's disease histone study diagram

Huntington's disease study

Huntington’s Disease

Histone deacetylase inhibitors (HDACi) inhibit the activity of histone deacetylases, keeping chromatin in an “active” euchromatin state, thereby promoting gene expression.









Cocaine addiction study diagram

Cocaine addiction study


Cocaine self-administration followed by 7 days of forced abstinence, increases BDNF expression in the prefrontal cortex by decreasing MeCP2 binding, and increasing phospho-CREB and histone acetylation at BDNF promoter IV.

Research Positions

Read about and apply for residency, fellowship and observership programs at

All applicants should register with the Mass General Careers Web site at Request a list of current open positions at


NCBI PubMed Publications


  1. Sadri-Vakili, G., Johnson, G.W., Janis, G.C., Gibbs, T.T., Pierce, R.C., and Farb, D.H. Inhibition of NMDA-induced striatal dopamine release and behavioral activation by the neuroactive steroid 3alpha-hydroxy-5beta-pregnan-20-one hemisuccinate.  Journal of Neurochemistry 2003; 86(1):92-101.
  2. Chen-Plotkin, A., Sadri-Vakili, G., Yohrling, G.J., Bravemen, M.W., Benn, C.L., Glajch, K.E., DiRocco, D.P., Farrell, L.A., Krainc, D., Gines, S., MacDonald, M., Cha, J.-H.J.  Decreased association of the transcription factor Sp1 with genes downregulated in Huntington’s disease.  Neurobiology of Disease 2006; 22(2):233-241.
  3. Sadri-Vakili, G. & Cha, J.-H.J. Mechanisms of disease: histone modifications in Huntington’s disease.  Nature Clinical Practice Neurology 2006; 2(6):330-338.
  4. Sadri-Vakili G., Menon, A.S., Farrell, L.A., Keller-McGandy, C.E., Cantuti-Castelvetri, I., Standaert, D.G., Augood, S.J., Yohrling, G.J., Cha, J.-H.J. Huntingtin inclusions do not down-regulate specific genes in the R6/2 Huntington’s disease mouse.  European Journal of Neuroscience 2006; 23(12):3171-3175.
  5. Sadri-Vakili, G. & Cha, J.-H.J. (2006) Histone deacetylase inhibitors: a novel    therapeutic approach to Huntington’s disease.  Current Alzheimer Research 3(4):403-408.
  6. 6. Sadri-Vakili, G., Bouzou, B., Benn, C.L., Kim, M., Chawla, P., Overland, R.P., Glajch, K.E., Xia, E., Qui, Z., Hersch, S.M., Clark, T.W., Yohrling, G.J., Cha, J.-H.J. Histones Associated with Downregulated Genes are Hypo-acetylated in Huntington’s Disease Models.  Human Molecular Genetics 2007; 16(11):1293-306.
  7. Anderson, S.M.*, Famous, K.R.*, Sadri-Vakili, G.*, Kumaresan, V.*,
    Schmidt, H.D., Bass, C., Terwilliger, Cha, J.-H.J. and Pierce, R.C.
    CaMKII: the biochemical bridge linking nucleus accumbens dopamine and glutamate systems in cocaine seeking. Nature Neuroscience 2008; 11(3):344-353.
    * Equal contribution.
  8. Kim, M., Chawla, P., Overland, R.P., Xia, E., Sadri-Vakili, G., Cha, J.-H.J. Mutant Huntingtin-mediated histone monoubiquitylation induces transcriptional dysregulation in Huntington’s disease. Journal of Neuroscience 2008; 28(15):3947-57.
  9. Broom, W.J., Greenway, M., Sadri-Vakili, G., Russ, C., Auwrter, K.E., Glajch, K.E., Swingler, R.J., Purcell, S., Sapp, P.C., McKenna-Yasek, D., Hosler, B.A., Horvitz, H.R., Glass, J.D., Cha, J.H.J., Hardiman, O., Brown Jr., R.H. 50bp deletion in the promoter for SOD1 promoter reduces SOD1 expression in vitro and correlates with population-specific increased age of onset in sporadic ALS. Amyotroph Lateral Sclerosis 2008; 9(4):229-37.
  10. Benn, C.L. and Sadri-Vakili, G., (2008) Misfolded huntingtin protein and implications for transcriptional dysregulation. Chapter in Protein Misfolding in Biology and Disease. Transworld Research Network. T.F. Outeiro (ed.)
  11. Benn, C.L., Sun, T., Sadri-Vakili, G., McFarland, K.N., DiRocco, D.P., Yohrling, G.J., Clark, T.W., Bouzou, B., Cha, J.-H.J. Huntingtin modulates transcription, occupies gene promoters in vivo and binds directly to DNA in a polyglutamine dependent manner. Journal of Neuroscience 2008; 28(42):10720-33.
  12. Sadri-Vakili, G., Janis, G.C., Pierce, R.C., Gibbs, T.T., and Farb, D.H. Physiological concentrations of pregnenolone sulfate increase extracellular dopamine in the rat striatum. Journal of Pharmacology and Experimental Therapeutics  2008; 327(3):840-5.
  13. Famous, K.R., Kumaresan, V., Sadri-Vakili, G., Schmidt, H.D., Mierke, D.F., Cha, J.-H.J., and Pierce, R.C. Phosphorylation-dependent trafficking of GluR2-containing AMPA receptors in the nucleus accumbens shell contributes to the reinstatement of cocaine seeking. Journal of Neuroscience 2008; 28(43):11061-70.
  14. Benn, C.L., Luthi-Carter, R., Kuhn A., Sadri-Vakili, G., Blankson, K.L., Dalai, S.C., Goldstein, D.R., Spires, T.L., Pritchard, J., Olson, J.M., van Dellen, A., Hannan, A.J., Cha, J.-H.J. Environmental enrichment reduces neuronal intranuclear inclusion load but has not effect on mRNA expression in a mouse model of Huntington’s disease. Journal of Neuropathology and Experimental Neurology 2010; 69(8):817-27.
  15. Sadri-Vakili, G., Kumaresan, V., Schmidt, H.D., Famous, K.R., Chawla, P., Vassoler, F., Xia, E., Overland, R.P., Bass, C.E., Terwilliger, E.F., Pierce, R.C., and Cha, J.H.J. Cocaine-induced chromatin remodeling increases brain-derived neurotrophic factor transcription in the rat medial prefrontal cortex, wihich alters the reinforcing efficacy of coaine. Journal of Neuroscience 2010; 30(35):11735-11744.
  16. McCarthy, D., Zhang, X., Darnell, S.B., Sangrey, G.R., Yanagawa, Y., Sadri-Vakili, G., and Bhide, P.G. (2011) Cocaine alters BDNF expression and neuronal migration in the embryonic mouse forebrain. Journal of Neuroscience 31:13400-13411.


Contact Us

MassGeneral Institute for Neurodegenerative Disease

Building 114, Charlestown Navy Yard

114 16th Street, Room 2003Mailcode: CNY B114-2-2003 Charlestown, MA 02129
  • Near Public Transit
  • Accessible
  • Phone: 617-726-2000
  • Fax: 617-724-1480

How to Apply for Positions

How to apply for jobs: Send an e-mail to to receive an automated e-mail with full instructions for all types of positions.

Fundraising Contact

Contact Krista McCabe in the Mass General Development office at 617-726-1392 or KMCCABE@PARTNERS.ORG.


Anne B. Young, MD, PhD
Director, Massgeneral Institute for Neurodegenerative Disease 
Professor of Neurology, Harvard Medical School

Clinical Appointments, Consultations & Clinical Trials

Please visit the main Neurology Service Contact page for all other contact information.

Lab Phone: 617-726-0332

Office Phone: 617-724-1487

MassGeneral Institute for Neurodegenerative Disease (MIND)

Back to Top