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Review
. 2019 Aug 29:11:25.
doi: 10.3389/fnsyn.2019.00025. eCollection 2019.

Depalmitoylation by Palmitoyl-Protein Thioesterase 1 in Neuronal Health and Degeneration

Kevin P Koster  1 , Akira Yoshii  1   2   3
Affiliations
Review

Depalmitoylation by Palmitoyl-Protein Thioesterase 1 in Neuronal Health and Degeneration

Kevin P Koster et al. Front Synaptic Neurosci. .

Abstract

Protein palmitoylation is the post-translational, reversible addition of a 16-carbon fatty acid, palmitate, to proteins. Protein palmitoylation has recently garnered much attention, as it robustly modifies the localization and function of canonical signaling molecules and receptors. Protein depalmitoylation, on the other hand, is the process by which palmitic acid is removed from modified proteins and contributes, therefore, comparably to palmitoylated-protein dynamics. Palmitoylated proteins also require depalmitoylation prior to lysosomal degradation, demonstrating the significance of this process in protein sorting and turnover. Palmitoylation and depalmitoylation serve as particularly crucial regulators of protein function in neurons, where a specialized molecular architecture and cholesterol-rich membrane microdomains contribute to synaptic transmission. Three classes of depalmitoylating enzymes are currently recognized, the acyl protein thioesterases, α/β hydrolase domain-containing 17 proteins (ABHD17s), and the palmitoyl-protein thioesterases (PPTs). However, a clear picture of depalmitoylation has not yet emerged, in part because the enzyme-substrate relationships and specific functions of depalmitoylation are only beginning to be uncovered. Further, despite the finding that loss-of-function mutations affecting palmitoyl-protein thioesterase 1 (PPT1) function cause a severe pediatric neurodegenerative disease, the role of PPT1 as a depalmitoylase has attracted relatively little attention. Understanding the role of depalmitoylation by PPT1 in neuronal function is a fertile area for ongoing basic science and translational research that may have broader therapeutic implications for neurodegeneration. Here, we will briefly introduce the rapidly growing field surrounding protein palmitoylation and depalmitoylation, then will focus on the role of PPT1 in development, health, and neurological disease.

Keywords: NMDA; PPT1; depalmitoylation; lipofuscinosis; neurodegeneration; palmitoylation.

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Figures

Figure 1
Figure 1
Palmitoyl-protein thioesterase 1 (PPT1) functions and dysfunction in infantile NCL (CLN1). (A) Substrates of PPT1 in peripheral cell types are depicted in their respective subcellular localization within the cell soma. Autophagy (including mitophagy) is depicted as flowing into the lysosome, where PPT1 depalmitoylates and contributes to the degradation of exhausted macromolecules. Arrows indicate depalmitoylation by PPT1 or the flow of materials into the lysosome. Red lines indicate the effect of PPT1-mediated depalmitoylation on localization of proteins, where the dotted lines represent reduced trafficking to one or another site. Both the vacuolar ATPase (V-ATPase; V0a1 subunit) and F1 complex of ATP synthase mislocalize to the plasma membrane in the absence of depalmitoylation by PPT1. (B) Example of the role of PPT1 in one well-defined mechanism of bioenergetic homeostasis. Left, under nutrient-rich conditions, TFEB is phosphorylated by mammalian target of rapamycin complex 1 (mTORC1) and does not enter the nucleus. Right, during starvation, mTORC1 disassociates from the lysosomal interface and cannot phosphorylate TFEB, which enters the nucleus to increases transcription of lysosomal biogenesis proteins and PPT1 (Jegga et al., ; Settembre et al., 2012). (C–H) Summary of the systems disrupted by loss of PPT1 that contribute to CLN1 progression. (C) Schematic demonstrating the spatiotemporal pattern of CLN1 disease pathology, which progresses in the characteristic pattern: thalamus > visual cortex > sensory cortices ≥ motor cortex (Kielar et al., 2007). The timeline of disease progression is also depicted in terms of disease phase (e.g., presymptomatic) and age of Ppt1−/− mice (in months). Gradients in (D–H) depict the relative timing of each pathology described. (D) In the earliest presymptomatic phase (i.e., in utero and neonatal), axonal and neurite connectivity is disrupted (Chu-LaGraff et al., ; Lange et al., 2018), potentially leading to dysfunctional circuit formation. (E) As early as 1-month, Ppt1−/− mice demonstrate reduced expression of critical pre-synaptic proteins (e.g., SNAP25) and abnormal expression of proteins associated with protection from Wallerian degeneration (Kielar et al., 2009). At 6-months, reductions in synaptic vesicle pool size are reported (Kim et al., 2008). (F) As early as postnatal day 33 (~1 month) structural and molecular defects of the postsynapse are detected in Ppt1−/− visual cortex that contributes to excitotoxicity (Koster et al., 2019). (G) Select GABAergic neuron populations begin to degenerate in the thalamus and cortex by 5 months (Kielar et al., 2007). These interneurons undergo robust degeneration by 7-months, preceding the onset of seizure (Kielar et al., 2007). (H) Beginning in the presymptomatic phase, significant astrocytosis is detected at 3-months in the thalamus, cortex, spinal cord, and cerebellum of Ppt1−/− mice. Astrocytosis becomes severe in the thalamus and robust in cortical regions by 5 months. At 7-months, astrocytosis is widespread and severe, while focal microglial activation is detected in both thalamus and cortex (Bible et al., ; Kielar et al., ; Macauley et al., ; Shyng et al., 2017).
Figure 2
Figure 2
Pre-synaptic and post-synaptic mechanisms regulated by PPT1. (A) In developing neurons, PPT1 depalmitoylates GAP43 and potentially collapsin response mediator protein 1 (CRMP1) at axonal growth cones (insets). Loss of PPT1 causes disruption or simplification of extending axons, although the mechanism remains unclear. (B) At the presynapse, PPT1 contributes to the local depalmitoylation of its substrates as well as to lysosomal degradation of expired proteins. Red lines indicate the effect of PPT1-mediated depalmitoylation on localization of proteins. Both VAMP2 and SNAP25 are trapped in the membrane in the absence of depalmitoylation by PPT1. PPT1 is illustrated in color code with its substrates. Pre-synaptic autophagy mechanisms also feed into the endo-lysosomal pathway (Liang, 2019), though the specific roles of PPT1 therein remain uncharacterized. (C–F) Loss of PPT1 causes post-synaptic dysregulation of dendritic spine morphology, NMDAR function, and calcium dynamics. (C) In the WT visual cortex, early-life visual experience triggers GluN2A expression and incorporation into synaptic NMDARs that are scaffolded by PSD-95 (Quinlan et al., 1999a,b). This incorporation generally occurs at the post-synaptic density of maturing dendritic spines, while GluN2B receptors are generally further from the synapse (van Zundert et al., 2004). (D) In the Ppt1−/− visual cortex, structurally immature synapses (filipodia and thin spines) incorporate primarily GluN2B-containing NMDARs and are scaffolded by SAP102. The overrepresentation of GluN2B-containing NMDARs results in higher levels of calcium into the extrasynaptic dendritic areas and induces excitotoxicity. (E) Magnification of red square in C. In WT neurons, basal GluN2B and Fyn palmitoylation maintain appropriate stability of GluN2B at the synaptic surface. (F) Magnification of red square in D. Loss of Ppt1−/− causes hyperpalmitoylation of both GluN2B and Fyn kinase, which leads to at least two potential mechanisms by which lack of PPT1 causes a delayed GluN2 subunit switch and disrupted calcium dynamics. Specifically, GluN2B-NMDARs may be overly stabilized at the synapse in Ppt1−/− neurons via: (i) hyperpalmitoylation of GluN2B may increase its half-life, promoting enhanced retention and local assembly of GluN2B-containing NMDARs at or near the synapse or (ii) hyperpalmitoylation of Fyn may enhance its local activity at the PSD, phosphorylating and stabilizing GluN2B at the synapse by restricting its AP-2-dependent endocytosis (Prybylowski et al., 2005). Protein names are listed next to their respective symbols/representations except where denoted with a dotted line.
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References

    1. Abrami L., Leppla S. H., van der Goot F. (2006). Receptor palmitoylation and ubiquitination regulate anthrax toxin endocytosis. J. Cell Biol. 172, 309–320. 10.1083/jcb.200507067 - DOI - PMC - PubMed
    1. Ahtiainen L., Luiro K., Kauppi M., Tyynelä J., Kopra O., Jalanko A. (2006). Palmitoyl protein thioesterase 1 (PPT1) deficiency causes endocytic defects connected to abnormal saposin processing. Exp. Cell Res. 312, 1540–1553. 10.1016/j.yexcr.2006.01.034 - DOI - PubMed
    1. Arnaud L., Ballif B. A., Förster E., Cooper J. A. (2003). Fyn tyrosine kinase is a critical regulator of disabled-1 during brain development. Curr. Biol. 13, 9–17. 10.1016/s0960-9822(02)01397-0 - DOI - PubMed
    1. Bagh M. B., Peng S., Chandra G., Zhang Z., Singh S. P., Pattabiraman N., et al. . (2017). Misrouting of v-ATPase subunit V0a1 dysregulates lysosomal acidification in a neurodegenerative lysosomal storage disease model. Nat. Commun. 8:14612. 10.1038/ncomms14612 - DOI - PMC - PubMed
    1. Barker-Haliski M., White S. H. (2015). Glutamatergic mechanisms associated with seizures and epilepsy. Cold Spring Harb. Perspect. Med. 5:a022863. 10.1101/cshperspect.a022863 - DOI - PMC - PubMed

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