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Progressive Retinal Degeneration and Glial Activation in the CLN6nclf Mouse Model of Neuronal Ceroid Lipofuscinosis: A Beneficial Effect of DHA and Curcumin Supplementation  [PDF]
Myriam Mirza, Cornelia Volz, Marcus Karlstetter, Monica Langiu, Aleksandra Somogyi, Mika O. Ruonala, Ernst R. Tamm, Herbert J?gle, Thomas Langmann
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0075963
Abstract: Neuronal ceroid lipofuscinosis (NCL) is a group of neurodegenerative lysosomal storage disorders characterized by vision loss, mental and motor deficits, and spontaneous seizures. Neuropathological analyses of autopsy material from NCL patients and animal models revealed brain atrophy closely associated with glial activity. Earlier reports also noticed loss of retinal cells and reactive gliosis in some forms of NCL. To study this phenomenon in detail, we analyzed the ocular phenotype of CLN6nclf mice, an established mouse model for variant-late infantile NCL. Retinal morphometry, immunohistochemistry, optokinetic tracking, electroretinography, and mRNA expression were used to characterize retinal morphology and function as well as the responses of Müller cells and microglia. Our histological data showed a severe and progressive degeneration in the CLN6nclf retina co-inciding with reactive Müller glia. Furthermore, a prominent phenotypic transformation of ramified microglia to phagocytic, bloated, and mislocalized microglial cells was identified in CLN6nclf retinas. These events overlapped with a rapid loss of visual perception and retinal function. Based on the strong microglia reactivity we hypothesized that dietary supplementation with immuno-regulatory compounds, curcumin and docosahexaenoic acid (DHA), could ameliorate microgliosis and reduce retinal degeneration. Our analyses showed that treatment of three-week-old CLN6nclf mice with either 5% DHA or 0.6% curcumin for 30 weeks resulted in a reduced number of amoeboid reactive microglia and partially improved retinal function. DHA-treatment also improved the morphology of CLN6nclf retinas with a preserved thickness of the photoreceptor layer in most regions of the retina. Our results suggest that microglial reactivity closely accompanies disease progression in the CLN6nclf retina and both processes can be attenuated with dietary supplemented immuno-modulating compounds.
A Murine Model of Variant Late Infantile Ceroid Lipofuscinosis Recapitulates Behavioral and Pathological Phenotypes of Human Disease  [PDF]
Jeremy P. Morgan, Helen Magee, Andrew Wong, Tarah Nelson, Bettina Koch, Jonathan D. Cooper, Jill M. Weimer
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0078694
Abstract: Neuronal ceroid lipofuscinoses (NCLs; also known collectively as Batten Disease) are a family of autosomal recessive lysosomal storage disorders. Mutations in as many as 13 genes give rise to ~10 variants of NCL, all with overlapping clinical symptomatology including visual impairment, motor and cognitive dysfunction, seizures, and premature death. Mutations in CLN6 result in both a variant late infantile onset neuronal ceroid lipofuscinosis (vLINCL) as well as an adult-onset form of the disease called Type A Kufs. CLN6 is a non-glycosylated membrane protein of unknown function localized to the endoplasmic reticulum (ER). In this study, we perform a detailed characterization of a naturally occurring Cln6 mutant (Cln6nclf) mouse line to validate its utility for translational research. We demonstrate that this Cln6nclf mutation leads to deficits in motor coordination, vision, memory, and learning. Pathologically, we demonstrate loss of neurons within specific subregions and lamina of the cortex that correlate to behavioral phenotypes. As in other NCL models, this model displays selective loss of GABAergic interneuron sub-populations in the cortex and the hippocampus with profound, early-onset glial activation. Finally, we demonstrate a novel deficit in memory and learning, including a dramatic reduction in dendritic spine density in the cerebral cortex, which suggests a reduction in synaptic strength following disruption in CLN6. Together, these findings highlight the behavioral and pathological similarities between the Cln6nclf mouse model and human NCL patients, validating this model as a reliable format for screening potential therapeutics.
Mechanisms of juvenile neuronal ceroid lipofuscinosis (JNCL)

遗传 , 2009,
Abstract: Juvenile neuronal ceroid lipofuscinosis (JNCL) is one type of the neuronal ceroid lipofuscinosis (NCLs), which is a group of pediatric neurodegenerative disorders. The symptoms of JNCL are retinal degeneration (rd), seizures, cognitive, and motor decline. The pathogenesis, summarized in this review, include apoptosis, autophagy, dysfunction in the structure associated with plasmalemma, oxidative stress and disruption of nitric oxide signaling, dysfunction of the mitochondrial and lysosome, unbalanced intracellular pH, and other relative mechanisms. Among them, only apoptosis and autophagy are well known. In apoptosis, the defects in CLN3 result in ceramide accumulation and upstream of mitochondrial membrane per-meabilization, which eventually induce caspase-dependent and caspase-independent cell death. Autophagy exists but is disrupted because the immaturity of autophagic vacuoles leads to the failure of autophagy circulation. Understanding of the pathogenesis, especially the pathways of cell death in JNCL, is helpful to explore the mechanism of neurodegenerative dis-orders, such as JNCL.
Late infantile neuronal ceroid lipofuscinosis: A case reports  [cached]
Ulu? Yi?,Semra H?z Kurul,Candan ?zo?ul,Eray Dirik
Turk Pediatri Ar?ivi , 2010,
Abstract: Neuronal ceroid lipofuscinoses are the most common neurodegenerative childhood-onset disorders characterized by autosomal recessive inheritance, epileptic seizures, progressive psychomotor deterioration, visual failure, and premature death. At least seven subtypes of childhood-onset neuronal ceroid lipofuscinoses have been identified of which the late-infantile-onset forms are genetically the most heterogeneous. We present a five-year-old girl with late infantile neuronal ceroid lipofuscinosis who presented with progressive psychomotor retardation, ataxia and epilepsia. Palmitoyl protein thioesterase activity was very low and a homozygous mutation was identified in CLN2 gene. (Turk Arch Ped 2010; 45: 155-7)
Juvenile neuronal ceroid lipofuscinosis: Clinical and radiological findings
Journal of Neurological Sciences , 2004,
Abstract: Neuronal ceroid lipofuscinoses, one of the causes of progressive myoclonus epilepsy, is characterized by the onset of rapid deterioration of vision, delayed psychomotor development, ataxia, hypotonia, epilepsy. Seizures are generalized tonic-clonic, complex-partial or myoclonic seizures. In the fundoscopic examination are shown pigmentary degeneration, optic atrophy and/or maculopathy. Nonselective diffuse cerebral and cerebellar atrophy were seen in cerebral imaging. We reported one patients, a 20-year-old female with progressive visual impairment. She had optic atrophy, seizures and abnormal EEG. Cerebral and cerebellar atrophy were seen in cerebral computed tomography.
Evidence for Aberrant Astrocyte Hemichannel Activity in Juvenile Neuronal Ceroid Lipofuscinosis (JNCL)  [PDF]
Maria Burkovetskaya, Nikolay Karpuk, Juan Xiong, Megan Bosch, Michael D. Boska, Hideyuki Takeuchi, Akio Suzumura, Tammy Kielian
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0095023
Abstract: Juvenile Neuronal Ceroid Lipofuscinosis (JNCL) is a lysosomal storage disease caused by an autosomal recessive mutation in CLN3 that leads to vision loss, progressive cognitive and motor decline, and premature death. Morphological evidence of astrocyte activation occurs early in the disease process and coincides with regions where neuronal loss eventually ensues. However, the consequences of CLN3 mutation on astrocyte function remain relatively ill-defined. Astrocytes play a critical role in CNS homeostasis, in part, by their ability to regulate the extracellular milieu via the formation of extensive syncytial networks coupled by gap junction (GJ) channels. In contrast, unopposed hemichannels (HCs) have been implicated in CNS pathology by allowing the non-discriminant passage of molecules between the intracellular and extracellular milieus. Here we examined acute brain slices from CLN3 mutant mice (CLN3Δex7/8) to determine whether CLN3 loss alters the balance of GJ and HC activity. CLN3Δex7/8 mice displayed transient increases in astrocyte HC opening at postnatal day 30 in numerous brain regions, compared to wild type (WT) animals; however, HC activity steadily decreased at postnatal days 60 and 90 in CLN3Δex7/8 astrocytes to reach levels lower than WT cells. This suggested a progressive decline in astrocyte function, which was supported by significant reductions in glutamine synthetase, GLAST, and connexin expression in CLN3Δex7/8 mice compared to WT animals. Based on the early increase in astrocyte HC activity, CLN3Δex7/8 mice were treated with the novel carbenoxolone derivative INI-0602 to inhibit HCs. Administration of INI-0602 for a one month period significantly reduced lysosomal ceroid inclusions in the brains of CLN3Δex7/8 mice compared to WT animals, which coincided with significant increases in astrocyte GJ communication and normalization of astrocyte resting membrane potential to WT levels. Collectively, these findings suggest that alterations in astrocyte communication may impact the progression of JNCL and could offer a potential therapeutic target.
A Critical Tryptophan and Ca2+ in Activation and Catalysis of TPPI, the Enzyme Deficient in Classic Late-Infantile Neuronal Ceroid Lipofuscinosis  [PDF]
Salomon Kuizon,Kathleen DiMaiuta,Marius Walus,Edmund C. Jenkins Jr,Marisol Kuizon,Elizabeth Kida,Adam A. Golabek,Daniel O. Espinoza,Raju K. Pullarkat,Mohammed A. Junaid
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0011929
Abstract: Tripeptidyl aminopeptidase I (TPPI) is a crucial lysosomal enzyme that is deficient in the fatal neurodegenerative disorder called classic late-infantile neuronal ceroid lipofuscinosis (LINCL). It is involved in the catabolism of proteins in the lysosomes. Recent X-ray crystallographic studies have provided insights into the structural/functional aspects of TPPI catalysis, and indicated presence of an octahedrally coordinated Ca2+.
Molecular epidemiology of childhood neuronal ceroid-lipofuscinosis in Italy  [cached]
Santorelli Filippo Maria,Garavaglia Barbara,Cardona Francesco,Nardocci Nardo
Orphanet Journal of Rare Diseases , 2013, DOI: 10.1186/1750-1172-8-19
Abstract: Background To review the descriptive epidemiological data on neuronal ceroid lipofuscinoses (NCLs) in Italy, identify the spectrum of mutations in the causative genes, and analyze possible genotype-phenotype relations. Methods A cohort of NCL patients was recruited through CLNet, a nationwide network of child neurology units. Diagnosis was based on clinical and pathological criteria following ultrastructural investigation of peripheral tissues. Molecular confirmation was obtained during the diagnostic procedure or, when possible, retrospectively. Results One hundred eighty-three NCL patients from 156 families were recruited between 1966 and 2010; 124 of these patients (from 88 families) were tested for known NCL genes, with 9.7% of the patients in this sample having not a genetic diagnosis. Late infantile onset NCL (LINCL) accounted for 75.8% of molecularly confirmed cases, the most frequent form being secondary to mutations in CLN2 (23.5%). Juvenile onset NCL patients accounted for 17.7% of this cohort, a smaller proportion than found in other European countries. Gene mutations predicted severe protein alterations in 65.5% of the CLN2 and 78.6% of the CLN7 cases. An incidence rate of 0.98/100,000 live births was found in 69 NCL patients born between 1992 and 2004, predicting 5 new cases a year. Prevalence was 1.2/1,000,000. Conclusions Descriptive epidemiology data indicate a lower incidence of NCLs in Italy as compared to other European countries. A relatively high number of private mutations affecting all NCL genes might explain the genetic heterogeneity. Specific gene mutations were associated with severe clinical courses in selected NCL forms only.
Systemic Administration of Tripeptidyl Peptidase I in a Mouse Model of Late Infantile Neuronal Ceroid Lipofuscinosis: Effect of Glycan Modification  [PDF]
Yu Meng, Istvan Sohar, Lingling Wang, David E. Sleat, Peter Lobel
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0040509
Abstract: Late-infantile neuronal ceroid lipofuscinosis (LINCL) is a recessive genetic disease of childhood caused by deficiencies in the lysosomal protease tripeptidyl peptidase I (TPP1). Disease is characterized by progressive and extensive neuronal death. One hurdle towards development of enzyme replacement therapy is delivery of TPP1 to the brain. In this study, we evaluated the effect of modifying N-linked glycans on recombinant human TPP1 on its pharmacokinetic properties after administration via tail vein injection to a mouse model of LINCL. Unmodified TPP1 exhibited a dose-dependent serum half-life of 12 min (0.12 mg) to 45 min (2 mg). Deglycosylation or modification using sodium metaperiodate oxidation and reduction with sodium borohydride increased the circulatory half-life but did not improve targeting to the brain compared to unmodified TPP1. Analysis of liver, brain, spleen, kidney and lung demonstrated that for all preparations, >95% of the recovered activity was in the liver. Interestingly, administration of a single 2 mg dose (80 mg/kg) of unmodified TPP1 resulted in ~10% of wild-type activity in brain. This suggests that systemic administration of unmodified recombinant enzyme merits further exploration as a potential therapy for LINCL.
Juvenile neuronal ceroid-lipofuscinosis: clinical and molecular investigation in a large family in Brazil
Valadares, Eugênia Ribeiro;Pizarro, Mayara Xavier;Oliveira, Luiz Roberto;Amorim, Regina Helena Caldas de;Pinheiro, Tarcísio Márcio Magalh?es;Grieben, Ulrike;Santos, Helena Hollanda;Queiroz, Rachel Rabelo;Lopes, Guilherme de Castro;Godard, Ana Lúcia Brunialti;
Arquivos de Neuro-Psiquiatria , 2011, DOI: 10.1590/S0004-282X2011000100004
Abstract: objective: juvenile neuronal ceroid-lipofuscinosis (jncl, cln 3, batten disease) (omim #204200) belongs to the most common group of neurodegenerative disorders of childhood. we report the clinical data and molecular analysis of a large brazilian family. method: family composed of two consanguineous couples and thirty-two children. clinical data of ten jncl patients and molecular analyses on 13 participants were obtained. results: the large 1.02 kb deletion was detected. the most severe phenotype, with autistic behavior, tics and parkinsonism was seen in a 12-year-old female and a milder phenotype in a 14-year-old male. nyctalopia was the first symptom in one deceased child. the visual loss of six patients has been first observed in the school and not at home. conclusion: the report highlights the phenotypical intrafamily variation in 10 affected children of this family. the molecular investigation of this large family in our metabolic center turned possible the diagnosis, right approach and genetic counseling.
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