Mutations in palmitoyl-protein thioesterase 1 alter exocytosis and endocytosis at synapses in<i>Drosophila</i>larvae

Aby, Elizabeth S.; Gumps, Katherine; Roth, Amalia; Sigmon, Stacey C.; Jenkins, Sarah E.; Kim, Joyce J.; Kramer, Nicholas J.; Parfitt, Karen D.; Korey, Christopher A.

doi:10.4161/fly.26630

Cited by 26 publications

(36 citation statements)

References 56 publications

(97 reference statements)

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“…The properties of PPT1 such as its neutral pH optimum and the lack of lysosomal processing to be functional [15], probably allows it to be enzymatically active in many subcellular compartments, including presynaptic termini [17, 18]. Moreover, PPT1, like CSP, has been shown to have a critical role in regulating the synaptic vesicle cycle, with PPT1 KO neurons exhibiting synaptic vesicle cycle deficits [1, 2, 17, 36]. Under normal conditions, PPT1 is likely to act on CSP at the synapse.…”

Section: Discussionmentioning

confidence: 99%

Neuronal ceroid lipofuscinosis with DNAJC5/CSPα mutation has PPT1 pathology and exhibit aberrant protein palmitoylation

et al. 2015

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Neuronal Ceroid Lipofuscinoses (NCL) are a group of inherited neurodegenerative disorders with lysosomal pathology (CLN1-14). Recently, mutations in the DNAJC5/CLN4 gene, which encodes the presynaptic co-chaperone CSP were shown to cause autosomal-dominant NCL. Although 14 NCL genes have been identified, it is unknown if they act in common disease pathways. Here we show that two disease-associated proteins, CSPα and the depalmitoylating enzyme palmitoyl-protein thioesterase 1 (PPT1/CLN1) are biochemically linked. We find that in DNAJC5/CLN4 patient brains, PPT1 is massively increased and mis-localized. Surprisingly, the specific enzymatic activity of PPT1 is dramatically reduced. Notably, we demonstrate that CSP is depalmitoylated by PPT1 and hence its substrate. To determine the consequences of PPT1 accumulation, we compared the palmitomes from control and DNAJC5/CLN4 patient brains by quantitative proteomics. We discovered global changes in protein palmitoylation, mainly involving lysosomal and synaptic proteins. Our findings establish a functional link between two forms of NCL and serve as a springboard for investigations of NCL disease pathways.

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Section: Discussionmentioning

confidence: 99%

Neuronal ceroid lipofuscinosis with DNAJC5/CSPα mutation has PPT1 pathology and exhibit aberrant protein palmitoylation

et al. 2015

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“…This agrees with previous observations in NPD and Pompe models of diminished clathrin-mediated uptake of ligands and cargo, including the mannose-6-phosphate receptor and recombinant therapeutic enzymes 28, 31 . Others have also reported deficits in synaptic neurotransmitter recycling, which depends on clathrin endocytosis 1 , in mouse models of glucocerebrosidase deficiency (characteristic of Gaucher and Parkinson’s disease) and palmitoyl protein thioesterase-1 deficiency (Batten disease) 26, 59 . This may contribute to the diminished synaptic plasticity, dopaminergenic neurotransmission, and other neurological symptoms observed in LSDs 6 .…”

Section: Discussionmentioning

confidence: 99%

A Comparative Study on the Alterations of Endocytic Pathways in Multiple Lysosomal Storage Disorders

et al. 2016

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Many cellular activities and pharmaceutical interventions involve endocytosis and delivery to lysosomes for processing. Hence, lysosomal processing defects can cause cell and tissue damage, as in lysosomal storage diseases (LSDs) characterized by lysosomal accumulation of undegraded materials. This storage causes endocytic and trafficking alterations, which exacerbate disease and hinder treatment. However, there have been no systematic studies comparing different endocytic routes or LSDs. Here, we used genetic and pharmacological models of four LSDs (type A Niemann-Pick, type C Niemann-Pick, Fabry, and Gaucher diseases) and evaluated the pinocytic and receptor-mediated activity of the clathrin-, caveolae-, and macropinocytic routes. Bulk pinocytosis was diminished in all diseases, suggesting a generic endocytic alteration linked to lysosomal storage. Fluid-phase (dextran) and ligand (transferrin) uptake via the clathrin route were lower for all LSDs. Fluid-phase and ligand (cholera toxin B) uptake via the caveolar route were both affected, but less acutely in Fabry or Gaucher diseases. EGF-induced macropinocytosis was altered in Niemann-Pick cells, not other LSDs. Intracellular trafficking of ligands was also distorted in LSD vs. wild-type cells. The extent of these endocytic alterations paralleled the level of cholesterol storage in disease cell lines. Confirming this, pharmacological induction of cholesterol storage in wild-type cells disrupted endocytosis, and model therapeutics restored uptake in proportion to their efficacy in attenuating storage. This suggests a proportional and reversible relationship between endocytosis and lipid (cholesterol) storage. By analogy, the accumulation of biological material in other diseases, or foreign material from drugs or their carriers, may cause similar deficits, warranting further investigation.

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“…Similarly, colocalization of caveolin-1 and clathrin heavy chain with their ligands (CTB and transferrin, respectively), as well as ligand uptake via these routes were enhanced proportionally to lysosomal storage reduction (Figure 7 and 27 ). Recent work using neuronal ceroid lipofuscinosis models have also demonstrated endocytic dysfunctions, despite genetic and lysosomal storage profiles different from NPD 58, 59 . Numerous factors may play a role, such as cytoskeletal abnormalities, impaired cytosolic diffusion of molecules, and/or altered lipid metabolism 19, 20, 22, 25, 48, 60 .…”

Section: Discussionmentioning

confidence: 99%

Altered Clathrin-Independent Endocytosis in Type A Niemann-Pick Disease Cells and Rescue by ICAM-1-Targeted Enzyme Delivery

et al. 2015

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Pharmaceutical intervention often requires therapeutics and/or their carriers to enter cells via endocytosis. Therefore, endocytic aberrancies resulting from disease represent a key, yet often overlooked, parameter in designing therapeutic strategies. In the case of lysosomal storage diseases (LSDs), characterized by lysosomal accumulation of undegraded substances, common clinical interventions rely on endocytosis of recombinant enzymes. However, the lysosomal defect in these diseases can affect endocytosis, as we recently demonstrated for clathrin-mediated uptake in patient fibroblasts with type A Niemann-Pick disease (NPD), a disorder characterized by acid sphingomylinase (ASM) deficiency and subsequent sphingomyelin storage. Using similar cells, we have examined if this is also the case for clathrin-independent pathways, including caveolae-mediated endocytosis and macropinocytosis. We observed impaired caveolin-1 enrichment at ligand-binding sites in NPD vs. wild type fibroblasts, corresponding with altered uptake of ligands and fluid-phase markers by both pathways. Similarly, aberrant lysosomal storage of sphingomyelin induced by pharmacological means also diminished uptake. Partial degradation of the lysosomal storage by untargeted recombinant ASM lead to partial uptake enhancement, while both parameters were restored to wild type levels by ASM delivery using model polymer nanocarriers specifically targeted to intercellular adhesion molecule-1 (anti-ICAM NCs). Carriers also restored caveolin-1 enrichment at ligand-binding sites and uptake through the caveolar and macropinocytic routes. These results demonstrate a link between lysosomal storage in NPD and alterations in clathrin-independent endocytosis, which could apply to other LSDs. Hence, this study shall guide the design of therapeutic approaches using viable endocytic pathways.

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Mutations in palmitoyl-protein thioesterase 1 alter exocytosis and endocytosis at synapses inDrosophilalarvae

Cited by 26 publications

References 56 publications

Neuronal ceroid lipofuscinosis with DNAJC5/CSPα mutation has PPT1 pathology and exhibit aberrant protein palmitoylation

Neuronal ceroid lipofuscinosis with DNAJC5/CSPα mutation has PPT1 pathology and exhibit aberrant protein palmitoylation

A Comparative Study on the Alterations of Endocytic Pathways in Multiple Lysosomal Storage Disorders

Altered Clathrin-Independent Endocytosis in Type A Niemann-Pick Disease Cells and Rescue by ICAM-1-Targeted Enzyme Delivery

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