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Identification of substrates of palmitoyl protein thioesterase 1 highlights roles of depalmitoylation in disulfide bond formation and synaptic function
Loss-of-function mutations in the depalmitoylating enzyme palmitoyl protein thioesterase 1 (PPT1) cause neuronal ceroid lipofuscinosis (NCL), a devastating neurodegenerative disease. The substrates of PPT1 are largely undescribed, posing a limitation on molecular dissection of disease mechanisms and therapeutic development. Here, Gorenberg et al. provide a resource identifying more than 100 novel PPT1 substrates. They used Acyl Resin-Assisted Capture (Acyl RAC) and mass spectrometry to identify proteins with increased in vivo palmitoylation in PPT1-deficient mouse brains, and then validated putative substrates through direct depalmitoylation with recombinant PPT1. Collectively, these data highlight the role of PPT1 in mediating synapse functions, implicate molecular pathways in the etiology of NCL and other neurodegenerative diseases, and advance our basic understanding of the purpose 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.
Image Credit: Betül Yücel
Citation: (2022) PLoS Biology Issue Image | Vol. 20(3) March 2022. PLoS Biol 20(3): ev20.i03. https://doi.org/10.1371/image.pbio.v20.i03
Published: March 31, 2022
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Loss-of-function mutations in the depalmitoylating enzyme palmitoyl protein thioesterase 1 (PPT1) cause neuronal ceroid lipofuscinosis (NCL), a devastating neurodegenerative disease. The substrates of PPT1 are largely undescribed, posing a limitation on molecular dissection of disease mechanisms and therapeutic development. Here, Gorenberg et al. provide a resource identifying more than 100 novel PPT1 substrates. They used Acyl Resin-Assisted Capture (Acyl RAC) and mass spectrometry to identify proteins with increased in vivo palmitoylation in PPT1-deficient mouse brains, and then validated putative substrates through direct depalmitoylation with recombinant PPT1. Collectively, these data highlight the role of PPT1 in mediating synapse functions, implicate molecular pathways in the etiology of NCL and other neurodegenerative diseases, and advance our basic understanding of the purpose 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.
Image Credit: Betül Yücel