Excitatory synapses in the central nervous system must simultaneously be plastic, in order to change their response properties over time, and stable, in order to persist for weeks to months, or even throughout an organism's lifetime. Defects in either property can lead to neurodevelopmental or neurodegenerative disorders, severely compromising cognition and quality of life. My laboratory studies the molecular mechanisms underlying these two critical yet seemingly contradictory synaptic properties. Our focus is on protein ubiquitination, a post-translational modification that targets proteins for degradation and has less-understood roles in coordinating their trafficking and binding interactions. At synapses, "regulated" ubiquitination is implicated in synapse formation/stabilization, neurotransmitter release, and plasticity mechanisms, while "dysregulated" ubiquitination is linked to synapse destabilization/loss and the etiology of several devastating neurodegenerative diseases. Accordingly, our two major areas of investigation are: 1) how ubiquitination regulates normal synaptic function, focusing on its roles in neurotransmitter release and receptor trafficking, and 2) how imbalances in synaptic ubiquitination disrupt protein homeostasis and lead to neurodegeneration. To address these questions, we perform gain and loss-of-function studies in primary neuronal cultures and hippocampal slices, using a sophisticated lentiviral delivery system, quantitative live-cell imaging, gene expression profiling, and biochemical analyses.
Waites CL, Mehta A, Tan PK, Thomas G, Edwards RH, Krantz DE (2001) An acidic motif retains vesicular monoamine transporter 2 on large dense core vesicles. J Cell Biol. 152(6):1159-68. PMID: 11257117.
Waites CL, Craig AM, Garner CC (2005) Mechanisms of vertebrate synaptogenesis. Ann Rev Neurosci. 28:251-74.
Li H, Waites CL, Staal RG, Dobryy Y, Park J, Sulzer DL, Edwards RH (2005) Sorting of vesicular monoamine transporter 2 to the regulated secretory pathway confers the somatodendritic exocytosis of monoamines. Neuron 48(4):619-33.
Regalado MP, Terry-Lorenzo RT, Waites CL, Garner CC, Malenka RC (2006) Transsynaptic signaling by postsynaptic synapse-associated protein 97. J Neurosci. 26(8): 2343-57.
Leal-Ortiz S*, Waites CL* (*contributed equally), Terry-Lorenzo R, Zamorano P, Gundelfinger ED, Garner CC (2008) Piccolo modulation of Synapsin1a dynamics regulates synaptic vesicle exocytosis. J Cell Biol. 181:831-846.
Waites CL*, Specht CG*, Haertel K, Leal-Ortiz S, Genoux D, Li D, Drisdel RC, Jeyifous O, Cheyne JE, Green WN, Montgomery JM, Garner CC (2009) Synaptic SAP97 isoforms regulate AMPA receptor dynamics and access to presynaptic glutamate. J Neurosci. 29(14):4332-4345.
Jeyifous O, Waites CL, Specht CG, Fujisawa S, Schubert M, Lin EI, Marshall J, Aoki C, de Silva T, Montgomery JM, Garner CC, Green WN (2009) SAP97 and CASK mediate sorting of NMDA receptors through a previously unknown secretory pathway. Nat Neurosci. 12(18):1011-9.
Waites CL, Garner CC (2011) Presynaptic function in health and disease. Trends Neurosci. 34(6): 326-37.
Hua Z, Leal-Ortiz SA, Foss SM, Waites CL, Garner CC, Voglmaier SM, and Edwards, RH (2011) v-SNARE composition distinguishes synaptic vesicle pools. Neuron. 71(3):474-87.
Waites CL, Leal-Ortiz SA, Andlauer TFM, Sigrist SJ, Garner CC. (2011) Piccolo regulates the dynamic assembly of presynaptic F-Actin. J Neurosci.31(40):14250-63.
Li D, Specht CG, Waites CL, Butler-Munro C, Leal-Ortiz SA, Foote JW, Genoux D, Garner CC, Montgomery JM (2011) SAP97 directs NMDA receptor spine targeting and synaptic plasticity. J Physiol. 589(18):4491-510.
Waites CL, Leal-Ortiz SA, Okerlund N, Dalke H, Fejtova A, Altrock WD, Gundelfinger ED, Garner CC (2013) Bassoon and Piccolo maintain synapse integrity by regulating protein ubiquitination and degradation. EMBO J., 32(7):954-69.
Honors and Awards
National Merit Scholarship1995
Graduated with Honors, Stanford University1994-95
Howard Hughes Medical Institute Undergraduate Research Grant1998-99
University of California Regents' Fellowship2002
Stanford University School of Medicine Dean's Fellowship2003-06
Ruth L. Kirschstein National Research Service Award (NIH-NINDS)