Disruption of<i>PPT1</i>or<i>PPT2</i>causes neuronal ceroid lipofuscinosis in knockout mice

Gupta, Praveena; Soyombo, Abigail A.; Atashband, Armita; Wisniewski, Krystyna E.; Shelton, John M.; Richardson, James A.; Hammer, Robert E.; Hofmann, Sandra L.

doi:10.1073/pnas.251485198

Cited by 267 publications

(320 citation statements)

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“…Furthermore, the C57BL/6J strain is highly inbred resulting in less variability between individuals than in outbred strains such as CD1. In addition, mouse models for other neuronal ceroid lipofuscinoses, including CLN1, CLN6, and CLN8, have been established on the C57BL/6J strain background (Gupta et al, 2001;Lei et al, 2006;Ranta et al, 1999;Wheeler et al, 2002). Having all mouse NCL mutant models on the same strain background will facilitate phenotypic comparisons between the different mutations.…”

Section: Discussionmentioning

confidence: 99%

Phenotypic characterization of a mouse model of juvenile neuronal ceroid lipofuscinosis

Katz

Johnson

Tullis

2008

Neurobiology of Disease

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Juvenile neuronal ceroid lipofuscinosis (JNCL) is an autosomal recessively inherited neurodegenerative disorder that results from mutations in the CLN3 gene. JNCL is characterized by accumulation of autofluorescent lysosomal storage bodies, vision loss, seizures, progressive cognitive and motor decline, and premature death. Studies were undertaken to characterize the neuronal ceroid lipofuscinosis phenotype in a Cln3 knockout mouse model. Progressive accumulation of autofluorescent storage material was observed in brain and retina of affected mice. The Cln3 -/-mice exhibited progressively impaired inner retinal function, altered pupillary light reflexes, losses of inner retinal neurons, and reduced brain mass. Behavioral changes included reduced spontaneous activity levels and impaired learning and memory. In addition, Cln3 -/-mice had significantly shortened life spans. These phenotypic features indicate that the mouse model will be useful for investigating the mechanisms underlying the disease pathology in JNCL and provide quantitative markers of disease pathology that can be used for evaluating the efficacies of therapeutic interventions.

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Section: Discussionmentioning

confidence: 99%

Phenotypic characterization of a mouse model of juvenile neuronal ceroid lipofuscinosis

Katz

Johnson

Tullis

2008

Neurobiology of Disease

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“…Details concerning the construction of the PPT2 knockout mouse strain have been reported (10). All studies were performed by using PPT2 homozygous knockout (or WT control) mice on a mixed C57BL͞6J ϫ 129S6͞SvEvTac background.…”

Section: Methodsmentioning

confidence: 99%

“…We had previously observed that PPT2 knockout mice begin to develop a neurological phenotype by 10 mo of age (10). We have now carried out observations of a large cohort of these animals for 24 mo.…”

Section: Ppt2 In Brain Tissues and Neurological Phenotype In Knockoutmentioning

confidence: 98%

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Disruption ofPPT2in mice causes an unusual lysosomal storage disorder with neurovisceral features

Gupta

Soyombo

Shelton

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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The palmitoyl protein thioesterase-2 (PPT2) gene encodes a lysosomal thioesterase homologous to PPT1, which is the enzyme defective in the human disorder called infantile neuronal ceroid lipofuscinosis. In this article, we report that PPT2 deficiency in mice causes an unusual form of neuronal ceroid lipofuscinosis with striking visceral manifestations. All PPT2-deficient mice displayed a neurodegenerative phenotype with spasticity and ataxia by 15 mo. The bone marrow was infiltrated by brightly autofluorescent macrophages and multinucleated giant cells, but interestingly, the macrophages did not have the typical appearance of foam cells commonly associated with other lysosomal storage diseases. Marked splenomegaly caused by extramedullary hematopoiesis was observed. The pancreas was grossly orange to brown as a result of massive storage of lipofuscin pigments in the exocrine (but not islet) cells. Electron microscopy showed that the storage material consisted of multilamellar membrane profiles (''zebra bodies''). In summary, PPT2 deficiency in mice manifests as a neurodegenerative disorder with visceral features. Although PPT2 deficiency has not been described in humans, manifestations would be predicted to include neurodegeneration with bone marrow histiocytosis, visceromegaly, brown pancreas, and linkage to chromosome 6p21.3 in affected families. P almitoyl protein thioesterase (PPT) 2 is a lysosomal thioesterase that is 27% identical to PPT1, a lysosomal enzyme defective in a neurodegenerative disorder called infantile neuronal ceroid lipofuscinosis, or infantile Batten disease (1). The neuronal ceroid lipofuscinosis (NCLs) are a group of neurodegenerative disorders of children characterized by the accumulation of autofluorescent storage material in the brain and other tissues, cognitive and motor deterioration, visual failure, and seizures. Notable is the absence of functionally significant manifestations outside the central nervous system (2, 3). The NCLs are caused by defects in at least eight genes (of which six have been identified), and different forms of the disease have a distinct storage ultrastructure (2). The PPT1 or CLN1 gene underlies the most severe form of the disease, and it encodes a thioesterase enzyme that removes palmitate or other fatty acids from cysteine residues in proteins (4-6). The enzyme encoded by PPT2 is a second lysosomal thioesterase with a substrate specificity that overlaps that of PPT1 (7-9).Recently, we disrupted both PPT1 and PPT2 genes in mice and showed that homozygous PPT1 knockout mice have a neurodegenerative disorder that closely parallels infantile Batten disease (10). Most PPT1 knockout mice are terminal by 10 mo of age. Preliminary analysis of homozygous PPT2 knockout mice at 10 mo had shown the development of scant autofluorescent storage material in the brain and a neurological phenotype in a proportion of the animals. In the current article, we have extended the observation of these PPT2 knockout mice throughout their natural lifespan and analyzed their behavio...

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“…The palmitoyl protein thioesterases, PPT1 and PPT2, are involved in degradation of lipid-modified proteins in lysosomes, with each having distinct substrate specificity due to divergence in the substrate-binding regions (Camp and Hofmann, 1993;Camp et al, 1994;Soyombo and Hofmann, 1997). Loss of either PPT1 or PPT2 function results in the accumulation of lipidmodified material characteristic of lysosomal storage disorders such as infantile neuronal ceroid lipofuscinosis (INCL), and ultimately leads to cell death (Vesa et al, 1995;Gupta et al, 2001Gupta et al, , 2003Mitchison et al, 2004). APT1 and APT2 have been associated with dynamic palmitate cycling.…”

Section: Enzymes Implicated In Protein Depalmitoylationmentioning

confidence: 99%

Emerging roles for protein S-palmitoylation in Toxoplasma biology

Frénal

Kemp

Soldati‐Favre

2014

International Journal for Parasitology

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a b s t r a c tPost-translational modifications are refined, rapidly responsive and powerful ways to modulate protein function. Among post-translational modifications, acylation is now emerging as a widespread modification exploited by eukaryotes, bacteria and viruses to control biological processes. Protein palmitoylation involves the attachment of palmitic acid, also known as hexadecanoic acid, to cysteine residues of integral and peripheral membrane proteins and increases their affinity for membranes. Importantly, similar to phosphorylation, palmitoylation is reversible and is becoming recognised as instrumental for the regulation of protein function by modulating protein interactions, stability, folding, trafficking and signalling. Palmitoylation appears to play a central role in the biology of the Apicomplexa, regulating critical processes such as host cell invasion which is vital for parasite survival and dissemination. The recent identification of over 400 palmitoylated proteins in Plasmodium falciparum erythrocytic stages illustrates the broad spread and impact of this modification on parasite biology. The main enzymes responsible for protein palmitoylation are multi-membrane protein S-acyl transferases harbouring a catalytic Asp-HisHis-Cys (DHHC) motif. A global functional analysis of the repertoire of protein S-acyl transferases in Toxoplasma gondii and Plasmodium berghei has recently been performed. The essential nature of some of these enzymes illustrates the key roles played by this post-translational modification in the corresponding substrates implicated in fundamental processes such as parasite motility and organelle biogenesis. Toward a better understanding of the depalmitoylation event, a protein with palmitoyl protein thioesterase activity has been identified in T. gondii. TgPPT1/TgASH1 is the main target of specific acyl protein thioesterase inhibitors but is dispensable for parasite survival, suggesting the implication of other genes in depalmitoylation. Palmitoylation/depalmitoylation cycles are now emerging as potential novel regulatory networks and T. gondii represents a superb model organism in which to explore their significance.

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Disruption ofPPT1orPPT2causes neuronal ceroid lipofuscinosis in knockout mice

Cited by 267 publications

References 33 publications

Phenotypic characterization of a mouse model of juvenile neuronal ceroid lipofuscinosis

Phenotypic characterization of a mouse model of juvenile neuronal ceroid lipofuscinosis

Disruption ofPPT2in mice causes an unusual lysosomal storage disorder with neurovisceral features

Emerging roles for protein S-palmitoylation in Toxoplasma biology

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