Yale/NIDA Neuroproteomics Center Publications
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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).
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).