研究领域
Our laboratory is interested in how synaptic activity modulates the molecular make-up of synaptic connections in the mammalian central nervous system (CNS), which in many cases leads to long-lasting changes in synaptic efficacy. The concerted regulation of protein synthesis and degradation is fundamental for the control of diverse cellular events. Many studies have provided evidence that new protein synthesis likely takes place at synapses and is required for plasticity. Protein degradation, on the other hand, provides another way to regulate protein levels. In fact the ability to dynamically control protein levels allows for very tight control of rapid signaling cascades.
We study the ubiquitin-proteasome system (UPS), one of the major cellular pathways controlling protein turnover in mammalian cells. The UPS is a complex proteolytic pathway whereby proteins are targeted to the 26S proteasome for degradation. Ubiquitin is covalently attached to a target protein through a series of steps: first an E1 ubiquitin activating enzymes pass ubiquitin to E2 transferase and E3 ligases. At this point, many times in concert with the help of an E2 enzyme, the E3 ligase binds and modifies the target protein with the ubiquitin. Multiple ubiquitin molecules are added and the protein is recognized and degraded by the 26S proteasome. Many cellular roles have been defined for the UPS such as cell cycle control, cell fate and growth determination, antigen presentation, and many cell signaling pathways. In contrast the mechanisms of how the UPS regulates the growth and development, maintenance, and remodeling of synaptic connection in the mammalian central nervous system (CNS) is less understood.
An interesting problem is how activated synapses of a single neuron become selectively modified as a result of synaptic plasticity. It is known, for example, that synaptic modifications can occur selectively at one group of synapses, but not at another group of synapses on the same neuron. This property is known as "input-" or "synapse specificity". It is plausible that the selective degradation of proteins that restrict or limit plasticity may be required for these synaptic changes to occur. Alternatively, various proteolytic activities may provide specificity for long-term synaptic changes. This could be accomplished through the degradation of some proteins at specific locations or by targeting regulatory components of a proteolytic pathway to modified or unmodified sites.
We study the UPS’s role in synaptic plasticity. One approach we take is to use genetically encoded fluorescent-based proteasome (or “degradation”) reporters and time-lapse confocal microscopy to assay how neuronal activity modulates the rate of degradation within the spines and dendrites of neurons. Using these techniques, we hope to understand how and why the UPS is activated at or recruited to synapses in response to neuronal activity.
We are also interested in identifying the protein targets of the UPS at synapses. In particular, we study how the UPS regulates alpha-amino-3-hydroxy-5-methyl-4-isoxaolepropionic acid (AMPA) type ionotropic glutamate receptor trafficking in neurons. The removal and insertion of AMPA receptors at glutamatergic synapses is one mechanism to either decrease or increase synaptic strength. We and others have found that the activity of the UPS is required for agonist-mediated endocytosis of AMPA receptors. The simple model is that protein degradation via the UPS is required for normal AMPA receptor trafficking in neurons. Using molecular and biochemical approaches, we hope to identify the components of the UPS and protein targets involved AMPA receptor trafficking.
We are also interested in neurodegenerative disease. In humans, many neurodegenerative diseases are characterized post-mortem by anatomical hallmarks visible by standard light microscopy. Alzheimer’s and Lewy body disease are the most common causes of dementia in elderly populations. These diseases are characterized by neurofibrillary tangles (NFT), plaques, and lewy bodies (large dense inclusions). Familial Parkinson’s disease is also characterized by Lewy bodies. In addition, large dense inclusions are characteristic of many of the CAG repeat diseases such as Huntington and ALS. Biochemical and immunohistochemical characterization of these inclusions, tangles, and neuritic plaques has indicated that they contain high concentrations of ubiquitin and ubiquitinated proteins. Does the ubiquitin-proteasome pathway contribute to these abnormalities and to neuronal death? We hope that the understanding of UPS in normal neuronal function will help elucidate how it may be involved in neuronal dysfunction and disease.
近期论文
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Kyriakakis P, Catanho M, Hoffner N, Thavarajah W, Hu VJ, Chao SS, Hsu A, Pham V, Naghavian L, Dozier LE, Patrick GN, Coleman TP. "Biosynthesis of Orthogonal Molecules Using Ferredoxin and Ferredoxin-NADP(+) Reductase Systems Enables Genetically Encoded PhyB Optogenetics." ACS Synth Biol. 2018 Feb 16;7(2):706-717.
Tong W, Dwyer CA, Thacker BE, Glass CA, Brown JR, Hamill K, Moremen KW, Sarrazin S, Gordts PLSM, Dozier LE, Patrick GN, Tor Y, Esko JD. "Guanidinylated Neomycin Conjugation Enhances Intranasal Enzyme Replacement in the Brain". Mol Ther. 2017 Dec 6;25(12):2743-2752.
Gonzales FR, Howell KK, Dozier LE, Anagnostaras SG, Patrick GN. Proteasome phosphorylation regulates cocaine-induced sensitization. Mol Cell Neurosci. 2017 Dec 5;88:62-69.
Goo, M.S., Sancho, L., Slepak, N.; Boassa, D.; Deerinck, T.J., Ellisman, M.H., Bloodgood, B.L., and Patrick, G.N.; "Activity-dependent trafficking of lysosomes in dendritic shaft and spine", J Cell Biol. 2017 Aug 7;216(8):2499-2513. (cover mention and top 10 neuroscience articles in JCB in 2017)
Marquez-Lona EM, Torres-Machorro AL, Gonzales FR, Pillus L, Patrick GN. "Phosphorylation of the 19S regulatory particle ATPase subunit, Rpt6, modifies susceptibility to proteotoxic stress and protein aggregation." PLoS One. 2017 Jun 29;12(6):e0179893.
Dwyer, C.A, Scudder, S.L., Lin, Y., Dozier, L.A., Phan; D., Allen, N. J., Patrick, G.N. and Jeffrey D., J.D. “Neurodevelopmental Changes in Excitatory Synaptic Structure and Function in the Cerebral Cortex of Sanfilippo Syndrome IIIA Mice” Sci Rep. 2017 Apr 18;7:46576.
Cifelli JL, Dozier L, Chung T, Patrick GN, Yang J. “Benzothiazole Amphiphiles Promote the Formation of Dendritic Spines in Primary Hippocampal Neurons.”J Biol Chem. (2016) Jun 3;291(23):11981-92 (cover article).
Rodrigues EM, Scudder SL, Goo MS, Patrick GN. Aβ-Induced Synaptic Alterations Require the E3 Ubiquitin Ligase Nedd4-1. J Neurosci. (2016) Feb 3;36(5):1590-5 (cover article).
Scudder SL, Patrick GN. Synaptic structure and function are altered by the neddylation inhibitor MLN4924. Mol Cell Neurosci. (2015) Mar;65:52-7.
Goo MS, Scudder SL, Patrick GN. Ubiquitin-dependent trafficking and turnover of ionotropic glutamate receptors. Front Mol Neurosci. (2015) Oct 16;8:60.
Scudder SL, Goo MS, Cartier AE, Molteni A, Schwarz LA, Wright R, Patrick GN. Synaptic strength is bidirectionally controlled by opposing activity-dependent regulation of Nedd4-1 and USP8. J Neurosci. (2014) Dec 10;34(50) (cover article).
Hamilton, A.M, Oh, W.C., Vega-Ramirez, H, Stein, I.S., Hell, J.W., Patrick, G.N., Zito, K. “Activity-dependent growth of new dendritic spines is regulated by the proteasome” (2012) Neuron Jun 21;74(6):1023-30
Anna E. Cartier, A.E., Ubhi, K., Spencer, B., Vazquez-Roque, R.A., Kosberg, K.A., Fourgeaud, L., Kanayson, P., Patrick, C., Rockenstein, E., Patrick, G.N., Masliah, E. “Differential Effects of UCHL1 Modulation on Alpha-Synuclein in PD-Like Models of Alpha-Synucleinopathy” (2012) PLoS One April 13: 7(4): e34713.
Djakovic, S.N., Marquez-Lona, E.M., Jakawich, S.K., Chu, C., Sutton, M.S., Patrick, G.N. “Phosphorylation of Rpt6 regulates proteasome function and synaptic strength” (2012) J. Neuroscience Apr 11;32(15):5126-31.
Schwarz, L.A., and Patrick, G.N. " Ubiquitin-dependent endocytosis, trafficking and turnover of neuronal membrane protein”. (2011) Mol Cell Neurosci 2012 Mar;49(3):387-93. Epub 2011 Aug 22.
Schwarz, L.A., Hall, B.J., and Patrick, G.N. "Activity-Dependent Ubiquitination of GluA1 Mediates a Distinct AMPAR Endocytosis and Sorting Pathway". (2010) J. Neuroscience 30(49):16718-29.
Keil, J, Shen, Zhouxin, Briggs, S, and Patrick, G.N. “Regulation of STIM1 and SOCE by the ubiquitin-proteasome system (UPS)" (2010) PLoS One Oct 18;5(10):e13465.
Jakawich S, Nealy R, Djakovic S, Patrick G.N., Sutton M. The Ubiquitin Proteasome System mediates slow homeostatic changes in synaptic strength. (2010) Neuroscience 29;171(4):1016-31
Djakovic, S.N., Schwarz, L.A., DeMartino, G.N. and Patrick, G.N., “Regulation of the Proteasome by Neuronal Activity and CaMKII” (2009) J. Biological Chemistry 284(39):26655-65.
Cartier, A.E., Djakovic, S.N., Wilson, S. and Patrick, G.N. “Regulation of synapse structure by the ubiquitin c-terminal hydrolase UCH-L1”. (2009) J. Neuroscience 29(24):7857-7868
Kerjan G, Han E, Dube C, Djakovic S, Patrick G.N., Baram T, Heinemann S, Gleeson J. Mice lacking doublecortin and doublecortin-like kinase 2 display altered hippocampal neuronal maturation and spontaneous seizures.(2009) Proc Natl Acad Sci U S A. Apr 21;106(16):6766-71. Epub 2009 Apr 2.
Patrick G.N. “Synapse formation and plasticity: recent insights from the perspective of the ubiquitin proteasome system.” (2006) Current opinion in neurobiology Feb;16(1):90-4 ; Jan 18; [Epub ahead of print]
Patrick, G.N., Bingol, B., Weld, H., Schuman, E.M., Ubiquitin-mediated proteasome activity is required for agonist-induced endocytosis of GluRs. (2003) Curr Biol. 2003 Dec 2;13(23):2073-81
Zukerberg, L.R.*, Patrick, G.N., Nikolic, M., Humbert, S., Lanier, L.M., Gertler, F.B., Vidal, M., Van Etten, R.A. & Tsai, L.-H-. Cables links Cdk5 and c-Abl, Facilitating Cdk5 Tyrosine Phosphorylation and Stimulation of Kinase Activity. (2000) Neuron Jun;26(3):633-46.
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