Roles of palmitoylation in axon growth, degeneration and regeneration

Holland, Sabrina M.; Thomas, Gareth M.

doi:10.1002/jnr.24003

Cited by 25 publications

(18 citation statements)

References 125 publications

(184 reference statements)

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“…Although an overexpression and a loss-of-function models cannot be compared straightforwardly, our findings bring an evidence on the effects of dysregulated networks of genes coding for palmitoylated proteins in relation to the process of axonal sprouting and proliferation in this CLN1 /PPT1- related experimental model. These findings are supported by a recent study on the role of palmitoylation in axonal dynamics (Holland and Thomas, 2017 ). An overexpression of the depalmitoylating enzyme may unbalance the fine tuning of the S-acylation process, thereby perturbing palmitoylated membrane proteins, which in turn may impact the CLN1 disease pathogenesis.…”

Section: Discussionsupporting

confidence: 85%

The Networks of Genes Encoding Palmitoylated Proteins in Axonal and Synaptic Compartments Are Affected in PPT1 Overexpressing Neuronal-Like Cells

Pezzini

Bianchi

Benfatto

et al. 2017

Front. Mol. Neurosci.

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CLN1 disease (OMIM #256730) is an early childhood ceroid-lipofuscinosis associated with mutated CLN1, whose product Palmitoyl-Protein Thioesterase 1 (PPT1) is a lysosomal enzyme involved in the removal of palmitate residues from S-acylated proteins. In neurons, PPT1 expression is also linked to synaptic compartments. The aim of this study was to unravel molecular signatures connected to CLN1. We utilized SH-SY5Y neuroblastoma cells overexpressing wild type CLN1 (SH-p.wtCLN1) and five selected CLN1 patients’ mutations. The cellular distribution of wtPPT1 was consistent with regular processing of endogenous protein, partially detected inside Lysosomal Associated Membrane Protein 2 (LAMP2) positive vesicles, while the mutants displayed more diffuse cytoplasmic pattern. Transcriptomic profiling revealed 802 differentially expressed genes (DEGs) in SH-p.wtCLN1 (as compared to empty-vector transfected cells), whereas the number of DEGs detected in the two mutants (p.L222P and p.M57Nfs*45) was significantly lower. Bioinformatic scrutiny linked DEGs with neurite formation and neuronal transmission. Specifically, neuritogenesis and proliferation of neuronal processes were predicted to be hampered in the wtCLN1 overexpressing cell line, and these findings were corroborated by morphological investigations. Palmitoylation survey identified 113 palmitoylated protein-encoding genes in SH-p.wtCLN1, including 25 ones simultaneously assigned to axonal growth and synaptic compartments. A remarkable decrease in the expression of palmitoylated proteins, functionally related to axonal elongation (GAP43, CRMP1 and NEFM) and of the synaptic marker SNAP25, specifically in SH-p.wtCLN1 cells was confirmed by immunoblotting. Subsequent, bioinformatic network survey of DEGs assigned to the synaptic annotations linked 81 DEGs, including 23 ones encoding for palmitoylated proteins. Results obtained in this experimental setting outlined two affected functional modules (connected to the axonal and synaptic compartments), which can be associated with an altered gene dosage of wtCLN1. Moreover, these modules were interrelated with the pathological effects associated with loss of PPT1 function, similarly as observed in the Ppt1 knockout mice and patients with CLN1 disease.

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Section: Discussionsupporting

confidence: 85%

The Networks of Genes Encoding Palmitoylated Proteins in Axonal and Synaptic Compartments Are Affected in PPT1 Overexpressing Neuronal-Like Cells

Pezzini

Bianchi

Benfatto

et al. 2017

Front. Mol. Neurosci.

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“…(I) Representative stills, zooms, and kymographs of proximal and distal axons from N-terminal domain and NPY-GFP transfected neurons (2DIV). regulating processes like the establishment of axon-dendrite polarity or axon growth, guidance, and maintenance (Fukata and Fukata, 2010;Holland and Thomas, 2017). Taken together, results we present here lead us to the conclusion that palmitoylation/depalmitoylation cycles act as a novel mechanism to polarize MAPs neurons.…”

Section: Palmitoylation Is a Mechanism To Target Proteins To The Axonsupporting

confidence: 71%

Dynamic Palmitoylation Targets MAP6 to the Axon to Promote Microtubule Stabilization during Neuronal Polarization

Tortosa

Adolfs

Fukata

et al. 2017

Neuron

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Microtubule-associated proteins (MAPs) are main candidates to stabilize neuronal microtubules, playing an important role in establishing axon-dendrite polarity. However, how MAPs are selectively targeted to specific neuronal compartments remains poorly understood. Here, we show specific localization of microtubule-associated protein 6 (MAP6)/stable tubule-only polypeptide (STOP) throughout neuronal maturation and its role in axonal development. In unpolarized neurons, MAP6 is present at the Golgi complex and in secretory vesicles. As neurons mature, MAP6 is translocated to the proximal axon, where it binds and stabilizes microtubules. Further, we demonstrate that dynamic palmitoylation, mediated by the family of α/β Hydrolase domain-containing protein 17 (ABHD17A-C) depalmitoylating enzymes, controls shuttling of MAP6 between membranes and microtubules and is required for MAP6 retention in axons. We propose a model in which MAP6's palmitoylation mediates microtubule stabilization, allows efficient organelle trafficking, and controls axon maturation in vitro and in situ.

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“…Lipid modifications facilitate sorting of both soluble and transmembrane proteins to specialized membrane domains (Fukata & Fukata, 2010;Linder & Deschenes, 2007). Normal signaling relies on the proper localization of lipid-modified substrates to discrete microenvironments, necessary for the formation, maintenance, and function of polarized cells (Fukata & Fukata, 2010;Holland & Thomas, 2017;Linder & Deschenes, 2007). For example, neurons rely heavily on the precise and regulated localization of proteins within axonal and dendritic membrane compartments.…”

Section: Introductionmentioning

confidence: 99%

Spatial organization of palmitoyl acyl transferases governs substrate localization and function

Philippe

Jenkins

2019

Molecular Membrane Biology

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Protein palmitoylation is a critical posttranslational modification that regulates protein trafficking, localization, stability, sorting and function. In mammals, addition of this lipid modification onto proteins is mediated by a family of 23 palmitoyl acyl transferases (PATs). PATs often palmitoylate substrates in a promiscuous manner, precluding our understanding of how these enzymes achieve specificity for their substrates. Despite generous efforts to identify consensus motifs defining PAT-substrate specificity, it remains to be determined whether additional factors beyond interaction motifs, such as local palmitoylation, participate in PAT-substrate selection. In this review, we emphasize the role of local palmitoylation, in which substrates are palmitoylated and trapped in the same subcellular compartments as their PATs, as a mechanism of enzymesubstrate specificity. We focus here on non-Golgi-localized PATs, as physical proximity to their substrates enables them to engage in local palmitoylation, compared to Golgi PATs, which often direct trafficking of their substrates elsewhere. PAT subcellular localization may be an under-recognized, yet important determinant of PAT-substrate specificity that may work in conjunction or completely independently of interaction motifs. We also discuss some current hypotheses about protein motifs that contribute to localization of non-Golgi-localized PATs, important for the downstream targeting of their substrates.

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Roles of palmitoylation in axon growth, degeneration and regeneration

Cited by 25 publications

References 125 publications

The Networks of Genes Encoding Palmitoylated Proteins in Axonal and Synaptic Compartments Are Affected in PPT1 Overexpressing Neuronal-Like Cells

The Networks of Genes Encoding Palmitoylated Proteins in Axonal and Synaptic Compartments Are Affected in PPT1 Overexpressing Neuronal-Like Cells

Dynamic Palmitoylation Targets MAP6 to the Axon to Promote Microtubule Stabilization during Neuronal Polarization

Spatial organization of palmitoyl acyl transferases governs substrate localization and function

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