Chemical biology approaches in the study of neuropsychiatric disorders.
Massachusetts General Hospital
185 Cambridge St.
Boston, MA 02114
Lab Size: Between 5-10
Our lab uses experimental approaches at the intersection of chemical biology and stem cell biology in order to investigate cellular pathways relevant to neuropsychiatric disorders. We are interested in leveraging the power of small-molecule probes for the identification of disease signatures for neuropsychiatric disorders such as schizophrenia and bipolar disorder using patient-derived neurons generated from induced pluripotent cells (iPSCs). We differentiate iPSCs to cortical neurons and study differences in synaptic and dendritic spine biology in specific cortical neuron subtypes using super-resolution microscopy as well as high-resolution calcium imaging studies. We couple these studies with phosphoproteomic, metabolomic and gene-expression studies to delineate the nature of cellular process that are aberrant in disease. We undertake these experiments in the presence of cellular perturbation with sets of annotated small molecules, in order to uncover disease-related vulnerabilities in specific cellular pathways.
We are involved in a collaborative effort to develop new small-molecule potentiators of neuronal activity-dependent induction of Arc (Activity-regulated cytoskeleton-associated protein; Arg3.1) and investigate their effects on synaptic biology in human cortical neurons, in order to develop small molecules with pro-cognitive potential. By examining the differences in cognitive effects of current small molecules in clinical practice, we are designing a new set of analogs that will allow us to determine the specific chemical moieties that are involved in increasing Arc expression and enhancing cognition in neuropsychiatric disorders.
Another project in the laboratory includes the role that non-histone acetylation in synaptogenesis, with a particular focus on acetylation sites on beta-catenin and Akt. We use small-molecule probes designed for isoform-specific inhibition of different histone deacetylases (HDACs) to dissect the mechanisms underlying the effect of histone deacetylase 6 (HDAC6) on synaptic stabilization in human neurons.
Finally, we are interested in using small-molecule gene expression databases in order to identify compounds that have potential therapeutic potential. Along this line, we have identified a small molecule whose gene-expression profile is strongly anti-correlated to the gene-expression profile for Parkinson's Disease. We are undertaking studies in human iPSC-derived dopaminergic neurons to delineate the mechanistic underpinnings of neuroprotection of this compound in dopaminergic neurons.
Lysine Deacetylation by HDAC6 Regulates Kinase Activity of AKT in Human Neural Progenitor Cells.
J. Iaconelli, J. Lalonde, B. Watmuff, B. Liu, R. Mazitschek, S.J. Haggarty, R. Karmacharya
ACS Chemical Biology (2017) 12: 2139–48.
Gene Expression-Based Screen for Parkinson’s Disease Identifies GW8510 as a Neuroprotective Agent.
N. Wimalasena N, V. Q. Le, K. Wimalasena, S. L. Schreiber, R. Karmacharya
ACS Chemical Neuroscience. (2016) 7: 857-863.EndFragment
Disease Signatures for Schizophrenia and Bipolar Disorder Using Induced Pluripotent Stem Cells.
B. Watmuff, S. S. Berkovitch, J. H. Huang, J. Iaconelli , S. Toffel, R. Karmacharya
Molecular and Cellular Neuroscience (2016), 73:96-103.
Unbiased Metabolite Profiling of Schizophrenia Fibroblasts Under Stressful Perturbations Reveals Dysregulation of Plasmalogens and phosphatidylcholines.
J. H. Huang, H. Park, J. Iaconelli, S.S. Berkovitch, B. Watmuff, D. McPhie, D. Öngür, B. M. Cohen, C. B. Clish, R. Karmacharya
Journal of Proteome Research (2017) 16:481-93.
HDAC6 Inhibitors Increase Membrane Localization of beta-Catenin in Human iPSC-derived Neural Progenitor Cells by Modulating Lys-49 Acetylation.
J. Iaconelli, J.H. Huang, S.S. Berkovitch, S. Chattopadhyay, R. Mazitschek, S.L. Schreiber , S.J. Haggarty, R. Karmacharya
ACS Chemical Biology (2015) 10:883-90.