Yale/NIDA Neuroproteomics Center Publications

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PLoS Biology, 2022

Cover legend: Loss-of-function mutations in the depalmitoylating enzyme palmitoyl protein thioesterase 1 (PPT1) cause a devastating neurodegenerative disease, neuronal ceroid lipofuscinosis (NCL). The substrates of PPT1 are largely unknown, posing a limitation on molecular dissection of disease mechanisms and therapeutic development. This study used Acyl Resin-Assisted Capture and mass spectrometry to identify >100 novel PPT1 substrates with increased in vivo palmitoylation in PPT1-deficient mouse brains, and then validated putative substrates by direct depalmitoylation with recombinant PPT1. These data highlight the role of PPT1 in mediating synapse functions, implicate molecular pathways involved in NCL and advance our understanding of the function of depalmitoylation. The image shows a neuron lacking PPT1, stained for the neuronal marker MAP2 (blue), the synaptic marker synaptophysin (green), and a newly identified PPT1 substrate syncam 2 (red), a synaptic adhesion molecule. For more information see: Gorenberg et al. (2022) Identification of substrates of palmitoyl protein thioesterase 1 highlights roles of depalmitoylation in disulfide bond formation and synaptic function. PLoS Biol. 20(3): e3001590 (PMCID: PMC9004782).

Brain Sciences, 2021

Cover legend: Exosomes comprise a significant class of microvesicular bodies synthesized and secreted by different cell types in many tissues, including brain. Biomolecular cargo in exosomes consist of proteins, lipids, metabolites and microRNAs that reflect the physiological status of the cell-of-origin. The role of exosomes in pathogenesis and disease progression of neurodegenerative disorders is evident from their ability to transport pathogenetic proteins and to communicate signals between different brain cell types. The high sensitivity and specificity of MS/proteomics provides a valuable tool for identifying exosomal biomarker candidates. This review highlights advancements in exosome proteomics and its potential for identifying protein biomarkers for neurodegenerative and neuropsychiatric disorders. Image was created with BioRender.com. For more information see the article: Mathew, B., Mansuri, M.S., Williams, K., Nairn, A.C. (2021) Exosomes as emerging biomarker tools in neurodegenerative and neuropsychiatric disorders – A proteomics perspective. Brain Sciences, 11(2), 258 (PMCID: PMC7922222).

Journal of Neuroscience, 2014

Cover legend: Artistic rendition of αβγ-synuclein knockout synapses, showing a deficit in cholera toxin-HRP positive vesicles (black vesicles). This experiment in synuclein-null neurons supports a physiological role for α-synuclein in synaptic vesicle endocytosis. For more information see the article by Vargas, K.J., Makhani, S., Davis, T., Westphal, C., Castillo, P.E., and Chandra, S.S. (2014). Synucleins regulate the kinetics of synaptic vesicle endocytosis. J. Neuroscience 34(28), 9364-9376. (PMCID: PMC4087213)

Journal of Cell Biology, 2012

Cover legend: GFP-Farp1 (green) promotes the polymerization of F-actin (red) in dendritic spines, the postsynaptic protrusions of excitatory synapses. Cheadle and Biederer reveal that Farp1 works with the synaptic adhesion molecule SynCAM 1 to promote spine assembly and organize presynaptic active zones. The postsynaptic marker Shank is stained blue. For more information see the article by Cheadle, L., Biederer, T. (2012) The novel synaptogenic protein Farp1 links postsynaptic cytoskeletal dynamics and transsynaptic organization. J Cell Biol. 199(6):985-1001. (PMCID: PMC3518221)

Journal of Biological Chemistry, 2010

Cover legend: SynCAM adhesion molecules connect pre- and postsynaptic membranes to organize synapses. The cover image shows a SynCAM 2 homodimer (left) and a SynCAM 1/2 heterodimer (right) based on the crystal structure and crystal packing of the first SynCAM 2 immunoglobulin domain. The strength of these trans-synaptic interactions is modulated by N-glycans (red) that reduce SynCAM 2 adhesion, likely through steric hindrance. In contrast, N-glycans (brown) facing away from SynCAM 1 may restrict its conformational freedom and position it toward binding. For more information see the article by Fogel, A.I., Li, Y., Wang, Q., Lam, T.T., Modis, Y. and Biederer, T. (2010) N-Glycosylation at the SynCAM immunoglobulin interface modulates synaptic adhesion. J. Biol. Chem. 285: 34864-34874. (PMCID: PMC2966101)

Cell, 2009

Cover legend: K-Cl cotransporters (KCCs) control transmembrane electrolyte flux in a variety of physiologic settings, including the acute response to altered extracellular osmolarity. In this issue of Cell, Rinehart et al. (pp. 525–536) use targeted phosphoproteomics to reveal how phosphorylation at two conserved sites in KCCs controls their activity. The image depicts the activation of KCC3 in red blood cells in response to extracellular hypotonicity. KCC3 (blue) is shown embedded in the red blood cell membrane. Cotransporters that are phosphorylated at T991 and T1048 in the C terminus (highlighted in a white “flash”) are inactive, while those that are dephosphorylated at these sites are active, allowing K-Cl efflux from the cell and preventing cell swelling due to influx of water. For more information see the article by Rinehart, J., Maksimova, Y.D., Tanis, J.E., Stone, K.E., Hodson, C.A., Zhang, J, Risinger, M., Pan, W., Wu, D., Colangelo, C.M., Forbush, B., Joiner, C.H., Gulcicek, E.E., Gallagher, P.G., and Lifton, R.P. (2009) Sites of regulated phosphorylation that control K-Cl cotransporter activity. Cell. 138(3):525-36. (PMCID: PMC2811214)