About
Professor Heiman is on sabbatical during spring 2023.
Myriam Heiman received a B.A. in molecular biology from Princeton University, and a Ph.D. in biology from the Johns Hopkins University. She received her post-doctoral training at the Rockefeller University, working with Dr. Paul Greengard and Dr. Nathaniel Heintz. In 2011 she started her research group at MIT and the Picower and Broad Institutes. Myriam can be reached at mheiman@mit.edu.
Research
The mammalian brain is composed of hundreds of cell types, woven together in an intricate web. While beautiful, this complexity has hampered our ability to conduct molecular studies of individual cell types in situ. In an effort to untangle this complexity, researchers historically have grouped nerve cells (neurons) into classes based on morphology, anatomical location, and a small sampling of the molecules that they express. However, in the post-genome era, there is an opportunity to comprehensively identify all the molecules that distinguish cell classes in the brain. Such an undertaking could have major benefits: for example, in many neurological diseases, certain classes of cells display enhanced vulnerability and are the first to show signs of degeneration, but the basis of this enhanced vulnerability is not known. Factors responsible for cell-type-specific disease vulnerability could thus be exploited as therapeutic targets.
To study the molecular profiles of distinct nerve cell classes in situ, our lab makes use of Translating Ribosome Affinity Purification (TRAP) in transgenic mice. Briefly, TRAP mice express an enhanced green fluorescent protein (EGFP)-tagged ribosomal protein, EGFP-L10a, such that EGFP serves as a ribosomal affinity tag allowing the indirect immunopurification of all translated messenger RNAs (mRNAs). When the EGFP-L10a fusion construct is driven by genetic elements known to target a distinct cell type, the complete translated mRNA profile of that cell type, and only that cell type, can be discerned.
Neuronal profiling in mouse models of Huntington’s disease
A fascinating example of enhanced cell-type-specific disease vulnerability is seen in Huntington’s disease (HD), a monogenic neurodegenerative disease caused by expansion of CAG (glutamine-encoding) trinucleotide repeats in the huntingtin gene. In HD, medium-sized spiny neurons of the striatum are dramatically affected, and in late stages of this disease, most medium spiny neurons are lost. Eventually, other classes of neurons are also affected in HD, but striatal medium spiny neurons are among the earliest stricken. The enhanced vulnerability of medium spiny neurons cannot be explained merely by the pattern of huntingtin expression, as the huntingtin gene itself is expressed in many cells. Thus, medium spiny neurons may express other factors that make them especially susceptible to death in HD (or may fail to express factors that would make them more resistant). To identify such susceptibility factors, our lab is using TRAP to compare the molecular profiles of more resistant and more vulnerable cell populations in HD. The levels of factors that correlate with enhanced vulnerability will be genetically manipulated, and the impact of these changes on the phenotype of Huntington’s disease model mice will be assessed. The aim of this research is to identify protective factors that may alter the course of Huntington’s disease progression and reveal insights into medium spiny neuron physiology.
Neuronal profiling in mouse models of Parkinson’s disease
Another focus in our lab is a collaborative project aimed at understanding how long-term adaptations occur in the brain in response to the loss of a key neurotransmitter, dopamine. Specifically, the motor symptoms of Parkinson’s disease (PD) – including resting tremor, rigidity, akinesia, and postural instability – are seen upon dopamine depletion in the brain, resultant from the death of dopamine-producing cells in the substantia nigra. A standard treatment for PD is administration of levodopa, which can be converted to dopamine, and which works well in the short term to relieve symptoms. However, interestingly, over the long term, patients receiving levodopa develop debilitating side effects and, over time, this drug loses its efficacy. The lab is currently investigating the levodopa-induced changes that occur in one of the major cell classes that levodopa acts upon – medium spiny neurons in the striatum. The goal of this project is to identify the molecular basis of levodopa-induced side effects which may ultimately lead to therapeutic targets for the long-term treatment of a Parkinsonian state.
The mosaic nature of the brain reveals itself in the course of diseases, including Huntington’s and Parkinson’s disease, which preferentially strike particular cell types. Our lab is using cell-type specific profiling to identify the molecular basis of this differential vulnerability, in the hope of making progress towards new disease therapeutics, and continuing to unravel the complexity of the mammalian brain.
Teaching
7.29/9.09 Cellular Neurobiology
9.181J Developmental Neurobiology
Publications
Nie, D., Chen, Z., Julich, K., Robson, V., Di Nardo, A., Cheng, Y-C., Woolf, C., Heiman, M., Sahin, M. (2015) The Stress-Induced Atf3-gelsolin Cascade Underlies Dendritic Spine Deficits in Neuronal Models of Tuberous Sclerosis Complex. J. Neurosci. 35(30):10762-72.
Uematsu, K., Heiman, M., Zelenina, M., Padovan, J., Chait, B., Aperia, A., Nishi, A., Greengard, P. (2015) Protein kinase A directly phosphorylates metabotropic glutamate receptor 5 to modulate its function. J. Neurochem. 132(6):677-86.
Shema, R., Kulicke, R., Cowley, G., Stein, R., Root, D.E., Heiman, M. (2015) Synthetic Lethal Screening in the Mammalian Central Nervous System Identifies Gpx6 as a Modulator of Huntington’s Disease. Proc. Natl. Acad. Sci. U S A 112(1):268-72.
Sagi, Y., Heiman, M., Peterson, J.D., Musatov, S., Kaplitt, M.G., Surmeier, D.J., Heintz, N., Greengard, P. (2014) Nitric oxide regulates synaptic transmission between spiny projection neurons. Proc. Natl. Acad. Sci. U S A 111(49):17636-41.
Fieblinger, T., Graves, S.M., Sebel, L.E., Alcacer, C., Plotkin, J.L., Gertler, T.S., Chan, C.S., Heiman, M., Greengard, P., Cenci, M.A., Surmeier, D.J. (2014) Cell type-specific plasticity of striatal projection neurons in parkinsonism and L-DOPA-induced dyskinesia. Nature Communications 5:5316.
Heiman, M., Kulicke, R., Fenster, R.J., Greengard, P., Heintz, N. (2014) Cell-Type-Specific mRNA Purification by Translating Ribosome Affinity Purification (TRAP). Nature Protocols 9(6):1282-91.
Heiman, M., Heilbut, A., Francardo, V., Kulicke, R., Fenster, R.J., Kolaczyk, E.D., Mesirov, J.P., Surmeier, D.J., Cenci, M.A., Greengard, P. (2014) Molecular adaptations of striatal spiny projection neurons during levodopa-induced dyskinesia. Proc. Natl. Acad. Sci. U S A 111(12):4578-83.
Jordi, E., Heiman, M., Marion-Poll, L., Guermonprez, P., Cheng, S.K., Nairn, A.C., Greengard, P., Girault, J.A. (2013) Differential effects of cocaine on histone post-translational modifications in identified populations of striatal neurons. Proc. Natl. Acad. Sci. U S A 110(23):9511-6.
Lerner, A.G., Upton, J-P., Praveen, P.V.K., Ghosh, R., Nakagawa, Y., Igbaria, A., Shen, S., Nguyen, V., Backes, B.J., Heiman, M., Heintz, N., Greengard, P., Hui, S., Tang, Q., Trusina, A., Oakes, S.A., Papa, F.R. (2012) IRE1α induces thioredoxin-interacting protein to activate the NLRP3 inflammasome and promote programmed cell death during endoplasmic reticulum stress. Cell Metab. 16(2):250-64.
Chan, C.S., Peterson, J.D., Gertler, T.S., Glajch, K.E., Quintana, R.E., Cui, Q., Sebel, L.E., Plotkin, J.L., Shen, W., Heiman, M., Heintz, N., Greengard, P., Surmeier, D.J. (2012) Strain-Specific Regulation of Striatal Phenotype in Drd2-eGFP BAC Transgenic Mice. J. Neurosci. 32(27):9124-9132.
Santini, E., Heiman, M., Greengard, P., Valjent, E., Fisone, G. (2009) Inhibition of mTOR signaling in Parkinson's disease prevents L-DOPA-induced dyskinesia. Sci. Signal. 2(80):ra36.
Santini, E., Alcacer, C., Cacciatore, S., Heiman, M., Hervé, D., Greengard, P., Girault, J.A., Valjent, E., Fisone, G. (2009) L-DOPA activates ERK signaling and phosphorylates histone H3 in the striatonigral medium spiny neurons of hemiparkinsonian mice. J. Neurochem. 108(3):621-33.
Heiman, M., Schaefer, A., Gong, S., Peterson, J., Day, M., Ramsey, K., Saurez-Farinas, M., Schwarz, C., Stephan, D.A., Surmeier, D.J., Greengard, P., Heintz, N. (2008) A Translational Profiling Approach for the Molecular Characterization of CNS Cell Types. Cell 135:738-48.
Doyle, J.P., Dougherty, J.D., Heiman, M., Schmidt, E.F., Stevens, T.R., Ma, G., Bupp, S., Shrestha, P., Shah, R.D., Doughty M.L., Gong, S., Greengard, P., Heintz, N. (2008) Application of a Translational Profiling Approach for the Comparative Analysis of CNS Cell Types. Cell 135:749-762.
Flajolet, M., He, G., Heiman, M., Lin, A., Nairn, A. C., Greengard, P. (2007). Regulation of Alzheimer's disease amyloid-beta formation by casein kinase I. Proc. Natl. Acad. Sci. USA 104: 4159-4164.
Bonilla, M. and K. W. Cunningham (2003). Mitogen-activated protein kinase stimulation of Ca2+ signaling is required for survival of endoplasmic reticulum stress in yeast. Mol. Biol. Cell 14:4296-4305.
Bonilla, M., K. K. Nastase, and K. W. Cunningham (2002). Essential role of calcineurin in response to endoplasmic reticulum stress. EMBO J. 21(10): 2343-53.
King, S. J., Bonilla, M., Rodgers, M. E., Schroer, T. A. (2002). Subunit organization in cytoplasmic dynein subcomplexes. Protein Sci. 11(5):1239-50.
Bonilla, M. and K. W. Cunningham (2002). Calcium release and influx in yeast: TRPC and VGCC rule another kingdom. SciSTKE (127):PE17.
Locke, E. G., Bonilla, M., Liang, L., Takita, Y., Cunningham, K. W. (2000). A homolog of voltage-gated Ca2+ channels stimulated by depletion of secretory Ca2+ in yeast. Mol. Cell Biol. 20(18):6686-94.
Awards + Honors
Dr. Heiman's work has been recognized by several awards, including a Rockefeller University Women & Science post-doctoral award, an NIH/NIDA National Research Service Award, an NIH/NINDS EUREKA award, and a Bumpus Foundation Innovation Award, given to early-career investigators studying the causes and prevention of Parkinson’s disease.