Joan S. Steffan

picture of Joan S. Steffan

Associate Professor, Psychiatry & Human Behavior
School of Medicine

Ph.D., University of CA, San Diego, 1980, Physiology and Pharmacology

Phone: (949) 824-6365

University of California, Irvine
4056 Gross Hall / Stem Cell Research Center
University of CA, Irvine
Mail Code: 1705
Irvine, CA 92697
Research Interests
Neurodegeneration, Huntington's Disease, Alzheimer's Disease, Autophagy, Aging
Research Abstract
The focus of my research is to find therapies for neurodegenerative diseases of aging. I am a protein chemist, molecular biologist and yeast geneticist with an expertise in the study of protein-protein interactions, post-translational modifications, neurobiology, metabolism and transcription. My work has led me to the study of autophagy, a mechanism of protein and organelle clearance by the lysosome, and how it may decline with age contributing to neurodegenerative disease onset. I am currently studying roles for Huntingtin (mutated in Huntington’s disease) and APOE (a risk gene for Alzheimer’s disease) in selective autophagy important for maintaining brain health with aging, in hopes of finding therapeutic targets to treat these diseases.
Morozko EL, Smith-Geater C, Monteys AM, Pradhan S, Lim RG, Langfelder P, Kachemov M, Hill A, Stocksdale JT, Cullis PR, Wu J, Ochaba J, Miramontes R, Chakraborty A, Hazra TK, Lau A, St-Cyr S, Orellana I, Kopan L, Wang KQ, Yeung S, Leavitt BR, Reidling JC, Yang XW, Steffan JS, Davidson BL, Sarkar PS, Thompson LM. PIAS1 modulates striatal transcription, DNA damage repair, and SUMOylation with relevance to Huntington's disease. Proc Natl Acad Sci U S A. 2021 Jan 26;118(4). doi: 10.1073/pnas.2021836118. PubMed PMID: 33468657.
Chatterjee M, Steffan JS, Lukacsovich T, Marsh JL, Agrawal N. Serine residues 13 and 16 are key modulators of mutant huntingtin induced toxicity in Drosophila. Exp Neurol. 2020 Sep 14;:113463. doi: 10.1016/j.expneurol.2020.113463. [Epub ahead of print] PubMed PMID: 32941796.
Ochaba J, Fote G, Kachemov M, Thein S, Yeung SY, Lau AL, Hernandez S, Lim RG, Casale M, Neel MJ, Monuki ES, Reidling J, Housman DE, Thompson LM, Steffan JS. IKKß slows Huntington's disease progression in R6/1 mice. Proc Natl Acad Sci U S A. 2019 May 28;116(22):10952-10961. doi: 10.1073/pnas.1814246116. Epub 2019 May 14. PubMed PMID: 31088970; PubMed Central PMCID: PMC6561205.
Franich NR, Basso M, André EA, Ochaba J, Kumar A, Thein S, Fote G, Kachemov M, Lau AL, Yeung SY, Osmand A, Zeitlin SO, Ratan RR, Thompson LM, Steffan JS. Striatal Mutant Huntingtin Protein Levels Decline with Age in Homozygous Huntington's Disease Knock-In Mouse Models. J Huntingtons Dis. 2018;7(2):137-150. doi: 10.3233/JHD-170274. PubMed PMID: 29843246; PubMed Central PMCID: PMC6002862.
Kratter IH, Zahed H, Lau A, Tsvetkov AS, Daub AC, Weiberth KF, Gu X, Saudou F, Humbert S, Yang XW, Osmand A, Steffan JS, Masliah E, Finkbeiner S. Serine 421 regulates mutant huntingtin toxicity and clearance in mice. J Clin Invest. 2016 Sep 1;126(9):3585-97. doi: 10.1172/JCI80339. Epub 2016 Aug 15. PubMed PMID: 27525439; PubMed Central PMCID: PMC5004962.
Ochaba J, Monteys AM, O'Rourke JG, Reidling JC, Steffan JS, Davidson BL, Thompson LM. PIAS1 Regulates Mutant Huntingtin Accumulation and Huntington's Disease-Associated Phenotypes In Vivo. Neuron. 2016 May 4;90(3):507-20. doi: 10.1016/j.neuron.2016.03.016. Epub 2016 Apr 14. PubMed PMID: 27146268; PubMed Central PMCID: PMC4942306.
Ochaba J, Lukacsovich T, Csikos G, Zheng S, Margulis J, Salazar L, Mao K, Lau AL, Yeung SY, Humbert S, Saudou F, Klionsky DJ, Finkbeiner S, Zeitlin SO, Marsh JL, Housman DE, Thompson LM, Steffan JS. Potential function for the Huntingtin protein as a scaffold for selective autophagy. Proc Natl Acad Sci U S A. 2014 Nov 25;111(47):16889-94. doi: 10.1073/pnas.1420103111. Epub 2014 Nov 10. PubMed PMID: 25385587; PubMed Central PMCID: PMC4250109.
O'Rourke JG, Gareau JR, Ochaba J, Song W, Raskó T, Reverter D, Lee J, Monteys AM, Pallos J, Mee L, Vashishtha M, Apostol BL, Nicholson TP, Illes K, Zhu YZ, Dasso M, Bates GP, Difiglia M, Davidson B, Wanker EE, Marsh JL, Lima CD, Steffan JS, Thompson LM. SUMO-2 and PIAS1 modulate insoluble mutant huntingtin protein accumulation. Cell Rep. 2013 Jul 25;4(2):362-75. doi: 10.1016/j.celrep.2013.06.034. Epub 2013 Jul 18. PubMed PMID: 23871671; PubMed Central PMCID: PMC3931302.
Jia H, Kast RJ, Steffan JS, Thomas EA. Selective histone deacetylase (HDAC) inhibition imparts beneficial effects in Huntington's disease mice: implications for the ubiquitin-proteasomal and autophagy systems. Hum Mol Genet. 2012 Dec 15;21(24):5280-93. doi: 10.1093/hmg/dds379. Epub 2012 Sep 10. PubMed PMID: 22965876; PubMed Central PMCID: PMC3510756.
Steffan JS. Does Huntingtin play a role in selective macroautophagy?. Cell Cycle. 2010 Sep 1;9(17):3401-13. doi: 10.4161/cc.9.17.12718. PubMed PMID: 20703094; PubMed Central PMCID: PMC3047613.
Thompson LM, Aiken CT, Kaltenbach LS, Agrawal N, Illes K, Khoshnan A, Martinez-Vincente M, Arrasate M, O'Rourke JG, Khashwji H, Lukacsovich T, Zhu YZ, Lau AL, Massey A, Hayden MR, Zeitlin SO, Finkbeiner S, Green KN, LaFerla FM, Bates G, Huang L, Patterson PH, Lo DC, Cuervo AM, Marsh JL, Steffan JS. IKK phosphorylates Huntingtin and targets it for degradation by the proteasome and lysosome. J Cell Biol. 2009 Dec 28;187(7):1083-99. doi: 10.1083/jcb.200909067. Epub 2009 Dec 21. PubMed PMID: 20026656; PubMed Central PMCID: PMC2806289.
Gu X, Greiner ER, Mishra R, Kodali R, Osmand A, Finkbeiner S, Steffan JS, Thompson LM, Wetzel R, Yang XW. Serines 13 and 16 are critical determinants of full-length human mutant huntingtin induced disease pathogenesis in HD mice. Neuron. 2009 Dec 24;64(6):828-40. doi: 10.1016/j.neuron.2009.11.020. PubMed PMID: 20064390; PubMed Central PMCID: PMC2807408.
Aiken CT, Steffan JS, Guerrero CM, Khashwji H, Lukacsovich T, Simmons D, Purcell JM, Menhaji K, Zhu YZ, Green K, Laferla F, Huang L, Thompson LM, Marsh JL. Phosphorylation of threonine 3: implications for Huntingtin aggregation and neurotoxicity. J Biol Chem. 2009 Oct 23;284(43):29427-36. doi: 10.1074/jbc.M109.013193. Epub 2009 Aug 26. PubMed PMID: 19710014; PubMed Central PMCID: PMC2785575.
Green KN, Steffan JS, Martinez-Coria H, Sun X, Schreiber SS, Thompson LM, LaFerla FM. Nicotinamide restores cognition in Alzheimer's disease transgenic mice via a mechanism involving sirtuin inhibition and selective reduction of Thr231-phosphotau. J Neurosci. 2008 Nov 5;28(45):11500-10. doi: 10.1523/JNEUROSCI.3203-08.2008. PubMed PMID: 18987186; PubMed Central PMCID: PMC2617713.
Rockabrand E, Slepko N, Pantalone A, Nukala VN, Kazantsev A, Marsh JL, Sullivan PG, Steffan JS, Sensi SL, Thompson LM. The first 17 amino acids of Huntingtin modulate its sub-cellular localization, aggregation and effects on calcium homeostasis. Hum Mol Genet. 2007 Jan 1;16(1):61-77. doi: 10.1093/hmg/ddl440. Epub 2006 Nov 29. PubMed PMID: 17135277.
Steffan JS, Agrawal N, Pallos J, Rockabrand E, Trotman LC, Slepko N, Illes K, Lukacsovich T, Zhu YZ, Cattaneo E, Pandolfi PP, Thompson LM, Marsh JL. SUMO modification of Huntingtin and Huntington's disease pathology. Science. 2004 Apr 2;304(5667):100-4. doi: 10.1126/science.1092194. PubMed PMID: 15064418.
Steffan JS, Bodai L, Pallos J, Poelman M, McCampbell A, Apostol BL, Kazantsev A, Schmidt E, Zhu YZ, Greenwald M, Kurokawa R, Housman DE, Jackson GR, Marsh JL, Thompson LM. Histone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in Drosophila. Nature. 2001 Oct 18;413(6857):739-43. doi: 10.1038/35099568. PubMed PMID: 11607033.
Steffan JS, Kazantsev A, Spasic-Boskovic O, Greenwald M, Zhu YZ, Gohler H, Wanker EE, Bates GP, Housman DE, Thompson LM. The Huntington's disease protein interacts with p53 and CREB-binding protein and represses transcription. Proc Natl Acad Sci U S A. 2000 Jun 6;97(12):6763-8. doi: 10.1073/pnas.100110097. PubMed PMID: 10823891; PubMed Central PMCID: PMC18731.
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