Jeffrey L. Noebels, M.D., Ph.D.
Professor of Molecular and Human Genetics
Professor, Departments of Neurology and Neuroscience; Programs in Integrative Molecular and Biomedical Sciences and Translational Biology & Molecular Medicine
Director, Blue Bird Circle Developmental Neurogenetics Laboratory
B.A., Reed College, 1972
Ph.D., Stanford University, 1977
M.D., Yale University, 1981
Postdoc, Harvard Medical School, 1983
The principal research strategy in the Developmental Neurogenetics Laboratory is to apply mutational analysis to learn how genes regulate neuronal excitability and network synchronization within the mammalian central nervous system. Spontaneous and transgenic mutations that express neurological phenotypes in the mouse provide a valuable opportunity to identify excitability genes and examine their role in synaptic plasticity in the developing brain.
Brain wave (EEG) phenotypes emerge from altered neuronal signaling properties, and are of special interest. Six mouse mutants causing spike-wave synchronization of the neocortex have been discovered in our laboratory (tottering, lethargic, ducky, and stargazer, slow wave, and mocha) and are linked to mutations of voltage-gated calcium ion channels, AMPA receptor trafficking TARP subunits, a sodium hydrogen exchanger, and vesicular zinc trafficking. Study of these mice have led to the identification of novel members of the TARP gene family, and a new understanding of how related molecules rescue function and determine selective vulnerability within thalamocortical pathways. Other new mouse models for human epilepsy syndromes involving mutant ion channel, receptor, synaptic vesicle proteins, and transcription factors for interneuron migration are being analyzed to pinpoint the neural network and specific electrophysiological abnormalities characteristic of the human disorder. We are also exploring activity-induced changes of downstream gene expression and conditional gene silencing in epileptic brain to identify regulatory pathways that are critical mechanisms of disease progression. Some of these genes, such as those for glutamate and GABA transporters and apoptotic pathways suggest distinct mechanisms for seizure-induced excitotoxicity and cell death.
Our laboratory recently discovered that mouse models of Alheimer’s Disease show non-convulsive cortical hyperexcitability, heralding a paradigm change in understanding the basis for cognitive disorders in familial AD. We have also identified MAPT1, the gene for tau protein, as a critical modifier of AD-linked cognitive decline and epilepsy.
At present, mutant mouse models of inherited disorders in neuronal excitability are under investigation using the molecular anatomical techniques of in situ hybridization and immunohistochemistry, quantitative analysis of seizure-activated mRNAs, in vivo and in vitro cell physiology, and optical fluorescence measurements of ion channel activity in presynaptic terminals of mouse brain slices. These studies form the basis for development of strategies to selectively correct the tissue expression of neuronal gene errors early in development.
In collaboration with the Baylor Human Genome Sequencing Center and a $4.5 million NIH grant, our laboratory performed a large-scale translational genomic research study examining variants in human ion channel genes. The Human Channelopathy Project revealed extensive complexity of disease-linked genes, and we are currently evaluating the contribution of SNP patterns as well as copy number variation in several hundred ion channel subunit genes to the complex inheritance of neurological excitability disorders such as epilepsy. A second and related large collaborative NIH funded Center project focusing on risk prediction of variants in ion channel genes linked to neurocardiac phenotypes is underway.
- Holth JK, Bomben VC, Reed JG, Inoue T, Younkin L, Younkin SG, Pautler RG, Botas J, Noebels JL (2013). Tau loss attenuates neuronal network hyperexcitability in mouse and Drosophila genetic models of epilepsy. J. Neurosci. 33(4): 1651-9. PubMed PMID: 23345237
- Klassen T, Davis C, Goldman A, Burgess D, Chen T, Wheeler D, McPherson J, Bourquin T, Lewis L, Villasana D, Morgan M, Muzny D, Gibbs R, Noebels J (2011). Exome sequencing of ion channel genes reveals complex profiles confounding personal risk assessment in epilepsy. Cell 145(7): 1036-48. PubMed PMID: 21703448
- Zhu PJ, Huang W, Kalikulov D, Yoo JW, Placzek AN, Stoica L, Zhou H, Bell JC, Friedlander MJ, Krnjević K, Noebels JL, Costa-Mattioli M (2011). Suppression of PKR promotes network excitability and enhanced cognition by interferon-γ-mediated disinhibition. Cell 147(6): 1384-96. PubMed PMID: 22153080
- Qian J, Xu K, Yoo J, Chen TT, Andrews G, Noebels JL (2011). Knockout of Zn transporters Zip-1 and Zip-3 attenuates seizure-induced CA1 neurodegeneration. J. Neurosci. 31(1): 97-104. PubMed PMID: 21209194
- Glasscock E, Yoo JW, Chen TT, Klassen TL, Noebels JL (2010). Kv1.1 potassium channel deficiency reveals brain-driven cardiac dysfunction as a candidate mechanism for sudden unexplained death in epilepsy. J. Neurosci. 30(15): 5167-75. PubMed PMID: 20392939
- Goldman AM, Glasscock E, Yoo J, Chen TT, Klassen TL, Noebels JL (2009). Arrhythmia in heart and brain: KCNQ1 mutations link epilepsy and sudden unexplained death. Sci. Transl. Med. 1(2): 2ra6. PubMed PMID: 20368164
- Price MG, Yoo JW, Burgess DL, Deng F, Hrachovy RA, Frost JD Jr, Noebels JL (2009). A triplet repeat expansion genetic mouse model of infantile spasms syndrome, Arx(GCG)10+7, with interneuronopathy, spasms in infancy, persistent seizures, and adult cognitive and behavioral impairment. J. Neurosci. 29(27): 8752-63. PubMed PMID: 19587282
- Ernst WL, Zhang Y, Yoo JW, Ernst SJ, Noebels JL (2009). Genetic enhancement of thalamocortical network activity by elevating alpha 1g-mediated low-voltage-activated calcium current induces pure absence epilepsy. J. Neurosci. 29(6): 1615-25. PubMed PMID: 19211869
- Glasscock E, Qian J, Yoo J, Noebels JL (2007). Masking Epilepsy by Combining Two Epilepsy Genes. Nat. Neurosci. 10(12): 1554-8. PubMed PMID: 17982453
- Palop JJ, Chin J, Roberson ED, Wang J, Thwin MT, Ly NB, Yoo J, Ho KO, Yu GQ, Kreitzer A, Finkbeiner S, Noebels JL, Mucke L (2007). Aberrant excitatory neuronal activity and compensatory remodeling of inhibitory hippocampal circuits in mouse models of Alzheimer's disease. Neuron 55(5): 697-711. PubMed PMID: 17785178
Jeffrey L. Noebels, M.D., Ph.D.
Department of Neurology - Neurosensory Center
Baylor College of Medicine
One Baylor Plaza, MS NB320
Houston, TX, 77030, U.S.A.