Horwich, Arthur L - Yale University - Biological & Biomedical Sciences

个人简介

Horwich received undergraduate and M.D. degrees from Brown University, trained in Pediatrics at Yale, was then a postdoctoral fellow first at Salk Institute in the Tumor Virology Laboratory, and then in Genetics at Yale, then joined the Yale faculty. His work was initially involved with protein import into mitochondria and resulted in discovery of a "folding machine" inside mitochondria, Hsp60. He has used genetic, biochemical, and biophysical tools to study the mechanism of action of these ring shaped so-called chaperonin machines that provide essential assistance to protein folding in many cellular compartments. More recently he has focused on neurodegenerative disease as caused by protein misfolding, seeking to understand how misfolded SOD1 enzyme in the cytosol of motor neurons leads to one form of ALS. His lab is modeling mutant SOD1-linked ALS in mice transgenic for a mutant SOD1-YFP, the YFP moiety offering a fluorescent reporter of the mutant protein and “tag” for biochemical studies. The transgenic mutant strain presents YFP fluorescent aggregates in motor neurons by the time of weaning, develops muscle weakness, and paralyzes by 6 months of age. By contrast, a wtSOD1-YFP transgenic strain with the same amount of total SOD1-YFP protein in spinal cord remains asymptomatic even after two years, and the cord remains free of aggregates. The nature of injury to the motor system of the mutant mice is under study, particularly at the level of lower motor neurons, examining their dendritic arbors, cell bodies, axons, and neuromuscular junctions, using both morphologic and electrophysiologic approaches. What is the most immediate target of the misfolded protein, and at what level in the motor system? Notably, endogenous molecular chaperones, Hsc70 and Hsp110, associate with the misfolded protein – they are obviously not able to fully protect the system. Can their overexpression alter the progression of motor dysfunction? MD Brown University (1975) Intern and Resident Yale School of Medicine

研究领域

Amyotrophic Lateral Sclerosis; Genetics; Motor Neurons; Neurosciences; Pediatrics; Superoxide Dismutase; Protein Folding; Neurodegenerative Diseases

近期论文

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Unfolded DapA forms aggregates when diluted into free solution, confounding comparison with folding by the GroEL/GroES chaperonin system. Ambrose AJ, Fenton W, Mason DJ, Chapman E, Horwich AL. Unfolded DapA forms aggregates when diluted into free solution, confounding comparison with folding by the GroEL/GroES chaperonin system.FEBS Lett. 2015 Feb 13;589(4):497-9. doi: 10.1016/j.febslet.2015.01.008. Epub 2015 Jan 17. Selective degeneration of a physiological subtype of spinal motor neuron in mice with SOD1-linked ALS Hadzipasic M, Tahvildari B, Nagy M, Bian M, Horwich AL, McCormick DA. Selective degeneration of a physiological subtype of spinal motor neuron in mice with SOD1-linked ALSProc Natl Acad Sci U S A. 2014 Nov 25;111(47):16883-8. doi: 10.1073/pnas.1419497111. Epub 2014 Nov 10. Absence of lipofuscin in motor neurons of SOD1-linked ALS mice. Bandyopadhyay, U., Nagy, M., Fenton, W.A., and Horwich, A.L. (2014) Absence of lipofuscin in motor neurons of SOD1-linked ALS mice. Proc. Natl. Acad. Sci. USA 111, 11055-11060. Molecular chaperones in cellular protein folding: the birth of a field. Horwich AL. Cell. 2014 Apr 10;157(2):285-8. doi: 10.1016/j.cell.2014.03.029. Production of RNA for transcriptomic analysis from mouse spinal cord motor neuron cell bodies by laser capture microdissection. Bandyopadhyay U, Fenton WA, Horwich AL, Nagy M. J Vis Exp. 2014 Jan 13;(83):e51168. doi: 10.3791/51168. RNA-Seq profiling of spinal cord motor neurons from a presymptomatic SOD1 ALS mouse. Bandyopadhyay, U., Cotney, J., Nagy, M., Oh, S., Leng, J., Mahajan, M., Mane, S., Fenton, W.A., Noonan, J., and Horwich, A.L. (2013) RNA-seq profile of spinal cord motor neurons from a presymptomatic SOD1 ALS mouse. PLoS One. 2013;8(1):e53575. doi: 10.1371/journal.pone.0053575. Epub 2013 Jan 3. A biochemical screen for GroEL/GroES inhibitors. Johnson SM, Sharif O, Mak PA, Wang HT, Engels IH, Brinker A, Schultz PG, Horwich AL, Chapman E. Bioorg Med Chem Lett. 2014 Feb 1;24(3):786-9. doi: 10.1016/j.bmcl.2013.12.100. Epub 2014 Jan 2. Molecular chaperone Hsp110 rescues a vesicle transport defect produced by an ALS-associated mutant SOD1 protein in squid axoplasm. Song, Y., Nagy, M., Ni, W., Tyagi, N., Fenton, W.A., Lopez-Giraldez, F., Overton, J., Horwich, A.L., and Brady, S.T. (2013) Molecular chaperone Hsp110 rescues a vesicle transport defect produced by an ALS-associated mutant SOD1 protein in squid axoplasm. Proc. Natl. Acad. Sci. USA 110, 5428-5433. Chaperonin-mediated protein folding. Horwich AL. J Biol Chem. 2013 Aug 16;288(33):23622-32. doi: 10.1074/jbc.X113.497321. Epub 2013 Jun 26. Bioorg Med Chem Lett. 2014 Feb 1;24(3):786-9. doi: 10.1016/j.bmcl.2013.12.100. Epub 2014 Jan 2. Protein folding in the cell: an inside story. Horwich AL. Nat Med. 2011 Oct 11;17(10):1211-6. doi: 10.1038/nm.2468. No abstract available. Hydrogen-deuterium exchange in vivo to measure turnover of an ALS-associated mutant SOD1 protein in spinal cord of mice. Farr, G.W., Fenton, W.A., Ying, Z., and Horwich, A.L. (2011) Hydrogen-deuterium exchange in vivo to measure turnover of an ALS-associated mutant SOD1 protein in spinal cord of mice. Protein Science, July 20 doi:10.1002/pro.700 (Epub ahead of print) Progressive aggregation despite chaperone associations of a mutant SOD1-YFP in transgenic mice that develop ALS. Wang, J., Farr, G.W., Zeiss, C.J., Rodriguez-Gil, D.J., Wilson, J.H., Furtak, K., Rutkowski, D.T., Kaufman, R.J., Ruse, C.I., Yates, J.R. III, Perrin, S., Feany, M.B., and Horwich, A.L. (2009) Progressive aggregation despite chaperone associations of a mutant SOD1-YFP in transgenic mice with ALS. Proc. Natl. Acad. Sci. USA 106, 1392-1397. Chaperonin chamber accelerates protein folding through passive action of preventing aggregation.