Daniel TS Pak

Professor of Pharmacology
Ph.D., Molecular and Cellular Biology
University of California, Berkeley, 1997
(202) 687-8750
dtp6@georgetown.edu
My laboratory is interested in the molecular changes that occur at synapses in response to experience. We have focused on proteins associated (either directly or as downstream targets) with the NMDA subtype of glutamate receptor, an important mediator of many forms of synaptic plasticity and learning in mammals. We utilize a combination of approaches ranging from molecular biology and biochemistry to cell biology, imaging, and mouse genetics to address the following aspects of synaptic modification.
I. Dendritic spine size, motility, and morphology
Spines are small, actin-rich dendritic protrusions that form the sites of excitatory synaptic input in the mammalian CNS. Spines uniquely exhibit morphological rearrangement in response to activity and therefore have been proposed to represent structural correlates of long-term information storage. We have identified a key actin regulatory protein, SPAR, which associates with NMDA receptors and promotes dramatic enlargement of dendritic spines. We are currently testing the hypothesis that SPAR is required for activity-dependent growth of spines, and that this augmentation is important for memory formation or stabilization in vivo.
II. Regulation of synapse number
Because strength of synaptic transmission is intimately related to the density of synapses on a neuron, synaptogenesis and synapse loss are both expected to play important roles in controlling activity levels. We are studying an activity-inducible serine-threonine kinase of the polo family, SNK, which triggers synapse elimination via the phosphorylation and ubiquitin-mediated degradation of key postsynaptic proteins, including SPAR. We are generating mutants in SNK to determine the involvement of this kinase in various paradigms of synapse turnover: during neurodevelopment (e.g. “pruning�), learning (information editing), and in neurodegenerative disorders that are often characterized by excessive synapse loss.
III. Synaptic targeting of signaling enzymes
It is well established that protein kinases including protein kinase C (PKC) and cAMP-dependent protein kinase (PKA) play critical roles in NMDA receptor-dependent synaptic plasticity. However, the organization of these signaling microdomains remains unclear, particularly at glutamatergic synapses. Using yeast two-hybrid and biochemical approaches we are undertaking the identification of novel scaffolding and targeting infrastuctures for PKC and cAMP metabolic/responsive enzymes situated in molecular proximity to the NMDA receptor.
III. Activity-dependent changes in synaptic protein composition
A long-term interest of the lab is to understand at the proteomic level how synaptic stimulation alters synapse content. Following chemical bath applications to mimic particular patterns of synaptic activity, we are using combined biochemical purification of postsynaptic densities and microarray analysis to characterize two aspects of synaptic plasticity: the ensemble of proteins that rapidly translocates into synapses and may contribute to short-term plasticity, as well as the de novo gene expression that occurs on a longer timecourse that contributes to long-lasting synaptic modifications.
Selected Publications:
- André EA, Forcelli PA, Pak DT. What goes up must come down: homeostatic synaptic plasticity strategies in neurological disease. Future Neurol. Feb;13(1):13-21, 2018.
- Dunn R, Queenan BN, Pak DTS, Forcelli PA.. Divergent effects of levetiracetam and tiagabine against spontaneous seizures in adult rats following neonatal hypoxia. Epilepsy Res. Feb;140:1-7, 2018.
- Queenan BN, Dunn RL, Santos VR, Feng Y, Huizenga MN, Hammack RJ, Vicini S, Forcelli PA, Pak DTS. Kappa opioid receptors regulate hippocampal synaptic homeostasis and epileptogenesis. Epilepsia. Jan;59(1):106-122, 2018
- William Rebeck G, Pak DTS. A mobile APP for sharing contacts on your cell: An Editorial Highlight for ‘The physiological role of the amyloid precursor protein as an adhesion molecule in the developing nervous system’ on page 11. J Neurochem. Oct;143(1):9-10, 2017.
- Lee Y, Lee JS, Lee KJ, Turner RS, Hoe HS, Pak DT. Polo-like kinase 2 phosphorylation of amyloid precursor protein regulates activity-dependent amyloidogenic processing. Neuropharmacology. 117:387-400, 2017.
- Song JM, Sung YM, Nam JH, Yoon H, Chung A, Moffat E, Jung M, Pak DT, Kim J, Hoe HS. A Mercaptoacetamide-Based Class II Histone Deacetylase Inhibitor Increases Dendritic Spine Density via RasGRF1/ERK Pathway. J Alzheimers Dis.51(2):591-604, 2016.
- Queenan BN, Lee KJ, Tan H, Huganir RL, Vicini S, Pak DT. Mapping homeostatic synaptic plasticity using cable properties of dendrites. Neuroscience. 315:206-16, 2016. doi: 10.1016/j.neuroscience.2015.12.017. Epub, 2015.
- Lee NJ, Song JM, Cho HJ, Sung YM, Lee T, Chung A, Hong SH, Cifelli JL, Rubinshtein M, Habib LK, Capule CC, Turner RS, Pak DT, Yang J, Hoe HS. Hexa (ethylene glycol) derivative of benzothiazole aniline promotes dendritic spine formation through the RasGRF1-Ras dependent pathway.Biochim Biophys Acta. 1862(2):284-95, 2016. doi: 10.1016/j.bbadis.2015.12.007. Epub, 2015.
- Rozeboom AM, Queenan BN, Partridge JG, Farnham C, Wu JY, Vicini S, Pak DT. Evidence for glycinergic GluN1/GluN3 NMDA receptors in hippocampal metaplasticity. Neurobiol Learn Mem. 125:265-73, 2015. doi: 10.1016/j.nlm.2015.10.005. Epub, 2015.
- Lee KJ, Rhyu IJ, Pak DT. Synapses need coordination to learn motor skills. Rev Neurosci. 2014;25(2):223-30
- Song JM, DiBattista AM, Sung YM, Ahn JM, Turner RS, Yang J, Pak DT, Lee HK, Hoe HS. A tetra(ethylene glycol) derivative of benzothiazole aniline ameliorates dendritic spine density and cognitive function in a mouse model of Alzheimer’s disease. Exp Neurol. 2014 Feb;252:105-13
- Sohn YI, Lee NJ, Chung A, Saavedra JM, Scott Turner R, Pak DT, Hoe HS. Antihypertensive drug Valsartan promotes dendritic spine density by altering AMPA receptor trafficking. Biochem Biophys Res Commun. 2013 Oct 4;439(4):464-70
- Lee KJ, Park IS, Kim H, Greenough WT, Pak DT, Rhyu IJ.Motor skill training induces coordinated strengthening and weakening between neighboring synapses. J Neurosci. 2013 Jun 5;33(23):9794-9
- Megill A, Lee T, DiBattista AM, Song JM, Spitzer MH, Rubinshtein M, Habib LK, Capule CC, Mayer M, Turner RS, Kirkwood A, Yang J, Pak DT, Lee HK, Hoe HS. A tetra(ethylene glycol) derivative of benzothiazole aniline enhances Ras-mediated spinogenesis.J Neurosci. 2013 May 29;33(22):9306-18
- Lee KJ, Queenan BN, Rozeboom AM, Bellmore R, Lim ST, Vicini S, Pak DT. Mossy fiber-CA3 synapses mediate homeostatic plasticity in mature hippocampal neurons. Neuron. 77:99-114, 2013
- Shin SM, Zhang N, Hansen J, Gerges NZ, Pak DT, Sheng M, Lee SH. GKAP orchestrates activity-dependent postsynaptic protein remodeling and homeostatic scaling. Nat Neurosci. 15:1655-1666, 2012
- Queenan BN, Lee KJ, Pak DT. Wherefore art thou, homeo(stasis)? Functional diversity in homeostatic synaptic plasticity. Neural Plasticity. ID718203. 2012
- Dumanis SB, Chamberlain KA, Sohn YJ, Lee YJ, Guenette SY, Suzuki T, Mathews PM, Pak DT, Rebeck GW, Suh YH, Park HS, Hoe HS. FE65 as a link between VLDLR and APP to regulate their trafficking and processing. Mol Neurodegener. 7(1):9. 2012
- Rozeboom AM, Pak DT. Identification and functional characterization of polo-like kinase 2 autoregulatory sites. Neuroscience. 202:147-57. 2012
- Babus LW, Little EM, Keenoy KE, Minami SS, Chen E, Song JM, Caviness J, Koo SY, Pak DT, Rebeck GW, Turner RS, Hoe HS. Decreased dendritic spine density and abnormal spine morphology in Fyn knockout mice. Brain Res. 1415:96-102, 2011
- Rogers JT, Rusiana I, Trotter J, Zhao L, Donaldson E, Pak DT, Babus LW, Peters M, Banko JL, Chavis P, Rebeck GW, Hoe HS, Weeber EJ. Reelin supplementation enhances cognitive ability, synaptic plasticity, and dendritic spine density. Learn Mem. 18(9):558-64, 2011
- Lee KJ, Hoe HS, Pak DT. Plk2 Raps up Ras to subdue synapses. Small Gtpases. 2(3):162-166, 2011
- Lee KJ, Lee Y, Rozeboom A, Lee JY, Udagawa N, Hoe HS, Pak DT. Requirement for plk2 in orchestrated ras and rap signaling, homeostatic structural plasticity, and memory. Neuron. 69:957-73, Mar 10 2011.
- Dumanis SB, Cha HJ, Song JM, Trotter JH, Spitzer M, Lee JY, Weeber EJ, Turner RS, Pak DT, Rebeck GW, Hoe HS. ApoE receptor 2 regulates synapse and dendritic spine formation. PLoS One. 6:e17203, Feb 15 2011.
- Hoe HS, Lee HK, Pak DT. The Upside of APP at Synapses.CNS Neurosci Ther2010 Dec 27.[Epub ahead of print]
- Evers DM, Matta JA, Hoe HS, Zarkowsky D, Lee SH, Isaac JT, Pak DT. Plk2 attachment to NSF induces homeostatic removal of GluA2 during chronic overexcitation. Nat Neurosci 13:1199-207, 2010
- Lee KJ, Moussa CE, Lee Y, Sung Y, Howell BW, Turner RS, Pak DT, Hoe HS: Beta amyloid-independent role of amyloid precursor protein in generation and maintenance of dendritic spines. Neuroscience. 2010
- Minami SS, Cordova A, Cirrito JR, Tesoriero JA, Babus LW, Davis GC, Dakshanamurthy S, Turner RS, Pak DT, Rebeck GW, Paige M, Hoe HS: ApoE mimetic peptide decreases Abeta production in vitro and in vivo. Mol Neurodegener. 5:16, 2010
- Herrick S, Evers DM, Lee JY, Udagawa N, Pak DT: Postsynaptic PDLIM5/Enigma Homolog binds SPAR and causes dendritic spine shrinkage. Mol Cell Neurosci.43:188-200, 2010
- Minami SS, Sung YM, Dumanis SB, Chi SH, Burns MP, Ann EJ, Suzuki T, Turner RS, Park HS, Pak DT, Rebeck GW, Hoe HS: The cytoplasmic adaptor protein X11{alpha} and extracellular matrix protein Reelin regulate ApoE receptor 2 trafficking and cell movement.FASEB J. 24:58-69, 2010
- Hoe HS, Lee KJ, Carney RS, Lee J, Markova A, Lee JY, Howell BW, Hyman BT, Pak DT, Bu G, Rebeck GW: Interaction of reelin with amyloid precursor protein promotes neurite outgrowth. J Neurosci. 29:7459-73, 2009
- Lu XJ, Chen XQ, Weng J, Zhang HY, Pak DT, Luo JH, Du JZ: Hippocampal SPAR induces enhancement of learning and memory in postnatally hypoxia-exposed mice. Neuroscience. May 11, 2009
- Hoe HS, Lee JY, Pak DT: Combinatorial morphogenesis of dendritic spines and filopodia by SPAR and alpha-actinin2. Biochem Biophys Res Commun. 384:55-60, 2009
- Hoe HS, Fu Z, Makarova A, Lee JY, Lu C, Feng L, Pajoohesh-Ganji A, Matsuoka Y, Hyman BT, Ehlers MD, Vicini S, Pak DT, Rebeck GW: The effects of amyloid precursor protein on postsynaptic composition and activity. J Biol Chem. 284:8495-506, 2009
- Cartagena CM, Ahmed F, Burns MP, Pajoohesh-Ganji A, Pak DT, Faden AI, Rebeck GW: Cortical injury increases cholesterol 24S hydroxylase (Cyp46) levels in the rat brain. J Neurotrauma. 25:1087-98, 2008
- Seeburg DP, Feliu-Mojer M, Gaiottino J, Pak DT, Sheng M: Critical role of CDK5 and Polo-like kinase 2 in homeostatic synaptic plasticity during elevated activity. Neuron. 58:571-83, 2008
- Richter M, Murai KK, Bourgin C, Pak DT, Pasquale EB: The EphA4 receptor regulates neuronal morphology through SPAR-mediated inactivation of Rap GTPases. J Neurosci. 27:14205-15, 2007
- Hoe HS, Cooper MJ, Burns MP, Lewis PA, van der Brug M, Chakraborty G, Cartagena CM, Pak DT, Cookson MR, Rebeck GW: The metalloprotease inhibitor TIMP-3 regulates amyloid precursor protein and apolipoprotein E receptor proteolysis.J Neurosci. 27:10895-905, 2007
- Fu Z, Lee SH, Simonetta A, Hansen J, Sheng M, Pak DT: Differential roles of Rap1 and Rap2 small GTPases in neurite retraction and synapse elimination in hippocampal spiny neurons.J Neurochem. 100:118-31, 2007
- Dunah AW, Hueske E, Wyszynski M, Hoogenraad CC, Jaworski J, Pak DT, Simonetta A, Liu G, Sheng M: LAR receptor protein tyrosine phosphatases in the development and maintenance of excitatory synapses. Nat Neurosci. 8:458-67, 2005
- Pak DT, Sheng M: Targeted protein degradation and synapse remodeling by an inducible protein kinase. Science. 302:1368-73, 2003
- Pak DT, Yang S, Rudolph-Correia S, Kim E, Sheng M: Regulation of dendritic spine morphology by SPAR, a PSD-95-associated RapGAP.Neuron. 31:289-303, 2001
- Sheng M, Pak DT: Ligand-gated ion channel interactions with cytoskeletal and signaling proteins.Annu Rev Physiol. 62:755-78, 2000
- Sheng M, Pak DT: Glutamate receptor anchoring proteins and the molecular organization of excitatory synapses.Ann N Y Acad Sci. 868:483-93, 1999
- Huang DW, Fanti L, Pak DT, Botchan MR, Pimpinelli S, Kellum R: Distinct cytoplasmic and nuclear fractions of Drosophila heterochromatin protein 1: their phosphorylation levels and associations with origin recognition complex proteins. J Cell Biol. 142:307-18, 1998
- Pak DT, Pflumm M, Chesnokov I, Huang DW, Kellum R, Marr J, Romanowski P, Botchan MR: Association of the origin recognition complex with heterochromatin and HP1 in higher eukaryotes. Cell. 91:311-23, 1997
- Gossen M, Pak DT, Botchan MR: Drosophila Homolog of Yeast ORC: Correction. Science. 271:1349b, 1996
- Ehrenhofer-Murray AE, Gossen M, Pak DT, Botchan MR, Rine J: Separation of origin recognition complex functions by cross-species complementation. Science. 270:1671-4, 1995
- Gossen M, Pak DT, Hansen SK, Acharya JK, Botchan MR: A Drosophila homolog of the yeast origin recognition complex. Science. 270:1674-7, 1995
Click here to do a Medline Search for all publications of Daniel Pak.