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neuronal ceroid lipofuscinosis

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https://www.readbyqxmd.com/read/28506594/fingolimod-and-teriflunomide-attenuate-neurodegeneration-in-mouse-models-of-neuronal-ceroid-lipofuscinosis
#1
Janos Groh, Kristina Berve, Rudolf Martini
CLN diseases are rare lysosomal storage diseases characterized by progressive axonal degeneration and neuron loss in the CNS, manifesting in disability, blindness, and premature death. We have previously demonstrated that, in animal models of infantile and juvenile forms of CLN disease (CLN1 and CLN3, respectively), secondary neuroinflammation in the CNS substantially amplifies neural damage, opening the possibility that immunomodulatory treatment might improve disease outcome. First, we recapitulated the inflammatory phenotype, originally seen in mice in autopsies of CLN patients...
May 13, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28487519/retinal-degeneration-in-a-mouse-model-of-cln5-disease-is-associated-with-compromised-autophagy
#2
Henri Leinonen, Velta Keksa-Goldsteine, Symantas Ragauskas, Philip Kohlmann, Yajuvinder Singh, Ekaterina Savchenko, Jooseppi Puranen, Tarja Malm, Giedrius Kalesnykas, Jari Koistinaho, Heikki Tanila, Katja M Kanninen
The Finnish variant of late infantile neuronal ceroid lipofuscinosis (CLN5 disease) belongs to a family of neuronal ceroid lipofuscinosis (NCLs) diseases. Vision loss is among the first clinical signs in childhood forms of NCLs. Mutations in CLN5 underlie CLN5 disease. The aim of this study was to characterize how the lack of normal functionality of the CLN5 protein affects the mouse retina. Scotopic electroretinography (ERG) showed a diminished c-wave amplitude in the CLN5 deficient mice already at 1 month of age, indicative of pathological events in the retinal pigmented epithelium...
May 9, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28478735/gene-therapy-of-adult-neuronal-ceroid-lipofuscinoses-with-crispr-cas9-in-zebrafish
#3
Xiaomin Yao, Xiaowei Liu, Yaguang Zhang, Yuhao Li, Chengjian Zhao, Shaohua Yao, Yu-Quan Wei
Adult-Onset Neuronal Ceroid Lipofuscinosis (ANCL), one of the neuronal ceroid lipofuscinosis (NCLs), is an inherited neurodegenerative disorder with progressive neuronal dysfunction. Recently, mutations in DNAJC5 gene that encodes Cysteine-String protein Alpha (CSPα) have been reported to be associated with familial Autosomal-Dominant ANCL (AD-ANCL). Here, we constructed an ANCL transgenic zebrafish model expressing human mutant DNAJC5 (mDNAJC5) gene under the control of a zebrafish neuron-specific promoter...
May 6, 2017: Human Gene Therapy
https://www.readbyqxmd.com/read/28468312/induced-pluripotent-stem-cells-derived-from-a-cln5-patient-manifest-phenotypic-characteristics-of-neuronal-ceroid-lipofuscinoses
#4
Kristiina Uusi-Rauva, Tea Blom, Carina von Schantz-Fant, Tomas Blom, Anu Jalanko, Aija Kyttälä
Neuronal ceroid lipofuscinoses (NCLs) are autosomal recessive progressive encephalopathies caused by mutations in at least 14 different genes. Despite extensive studies performed in different NCL animal models, the molecular mechanisms underlying neurodegeneration in NCLs remain poorly understood. To model NCL in human cells, we generated induced pluripotent stem cells (iPSCs) by reprogramming skin fibroblasts from a patient with CLN5 (ceroid lipofuscinosis, neuronal, 5) disease, the late infantile variant form of NCL...
May 1, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28456380/a-basic-apoe-based-peptide-mediator-to-deliver-proteins-across-the-blood-brain-barrier-long-term-efficacy-toxicity-and-mechanism
#5
Yu Meng, Jennifer A Wiseman, Yuliya Nemtsova, Dirk F Moore, Jenieve Guevarra, Kenneth Reuhl, William A Banks, Richard Daneman, David E Sleat, Peter Lobel
We have investigated delivery of protein therapeutics from the bloodstream into the brain using a mouse model of late-infantile neuronal ceroid lipofuscinosis (LINCL), a lysosomal disease due to deficiencies in tripeptidyl peptidase 1 (TPP1). Supraphysiological levels of TPP1 are delivered to the mouse brain by acute intravenous injection when co-administered with K16ApoE, a peptide that in trans mediates passage across the blood-brain barrier (BBB). Chronic treatment of LINCL mice with TPP1 and K16ApoE extended the lifespan from 126 to >294 days, diminished pathology, and slowed locomotor dysfunction...
April 26, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28428354/multiplex-tandem-mass-spectrometry-enzymatic-activity-assay-for-newborn-screening-of-the-mucopolysaccharidoses-and-type-2-neuronal-ceroid-lipofuscinosis
#6
Yang Liu, Fan Yi, Arun Babu Kumar, Naveen Kumar Chennamaneni, Xinying Hong, C Ronald Scott, Michael H Gelb, Frantisek Turecek
BACKGROUND: We expanded the use of tandem mass spectrometry combined with liquid chromatography (LC-MS/MS) for multiplex newborn screening of seven lysosomal enzymes in dried blood spots (DBS). The new assays are for enzymes responsible for the mucopolysaccharidoses (MPS-I, -II, -IIIB, -IVA, -VI, and -VII) and type 2 neuronal ceroid lipofuscinosis (LINCL). METHODS: New substrates were prepared and char-acterized for tripeptidyl peptidase 1 (TPP1), α-N-acetylglucosaminidase (NAGLU), and lysosomal β-glucuronidase (GUSB)...
April 20, 2017: Clinical Chemistry
https://www.readbyqxmd.com/read/28404863/individuals-with-progranulin-haploinsufficiency-exhibit-features-of-neuronal-ceroid-lipofuscinosis
#7
Michael E Ward, Robert Chen, Hsin-Yi Huang, Connor Ludwig, Maria Telpoukhovskaia, Ali Taubes, Helene Boudin, Sakura S Minami, Meredith Reichert, Philipp Albrecht, Jeffrey M Gelfand, Andres Cruz-Herranz, Christian Cordano, Marcel V Alavi, Shannon Leslie, William W Seeley, Bruce L Miller, Eileen Bigio, Marek-Marsel Mesulam, Matthew S Bogyo, Ian R Mackenzie, John F Staropoli, Susan L Cotman, Eric J Huang, Li Gan, Ari J Green
Heterozygous mutations in the GRN gene lead to progranulin (PGRN) haploinsufficiency and cause frontotemporal dementia (FTD), a neurodegenerative syndrome of older adults. Homozygous GRN mutations, on the other hand, lead to complete PGRN loss and cause neuronal ceroid lipofuscinosis (NCL), a lysosomal storage disease usually seen in children. Given that the predominant clinical and pathological features of FTD and NCL are distinct, it is controversial whether the disease mechanisms associated with complete and partial PGRN loss are similar or distinct...
April 12, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28365442/loss-of-cln3-impacts-protein-secretion-in-the-social-amoeba-dictyostelium
#8
Robert J Huber
Neuronal ceroid lipofuscinosis (NCL), also referred to as Batten disease, is the most common form of childhood neurodegeneration. Mutations in CLN3 cause the most prevalent subtype of the disease, which manifests during early childhood and is currently untreatable. The precise function of the CLN3 protein is still not known, which has inhibited the development of targeted therapies. In the social amoeba Dictyostelium discoideum, loss of the CLN3 homolog, Cln3, reduces adhesion during early development, which delays streaming and aggregation...
March 29, 2017: Cellular Signalling
https://www.readbyqxmd.com/read/28365214/in-vivo-localization-of-the-neuronal-ceroid-lipofuscinosis-proteins-cln3-and-cln7-at-endogenous-expression-levels
#9
Alamin Mohammed, Megan B O'Hare, Alice Warley, Guy Tear, Richard I Tuxworth
The neuronal ceroid lipofuscinoses are a group of recessively inherited, childhood-onset neurodegenerative conditions. Several forms are caused by mutations in genes encoding putative lysosomal membrane proteins. Studies of the cell biology underpinning these disorders are hampered by the poor antigenicity of the membrane proteins, which makes visualization of the endogenous proteins difficult. We have used Drosophila to generate knock-in YFP-fusions for two of the NCL membrane proteins: CLN7 and CLN3. The YFP-fusions are expressed at endogenous levels and the proteins can be visualized live without the need for overexpression...
March 29, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/28345005/chronic-enzyme-replacement-to-the-brain-of-a-late-infantile-neuronal-ceroid-lipofuscinosis-mouse-has-differential-effects-on-phenotypes-of-disease
#10
Jennifer A Wiseman, Yu Meng, Yuliya Nemtsova, Paul G Matteson, James H Millonig, Dirk F Moore, David E Sleat, Peter Lobel
Late infantile neuronal ceroid lipofuscinosis (LINCL) is a fatal inherited neurodegenerative disease caused by loss of lysosomal protease tripeptidyl peptidase 1 (TPP1). We have investigated the effects of chronic intrathecal (IT) administration using enzyme replacement therapy (ERT) to the brain of an LINCL mouse model, in which locomotor function declines dramatically prior to early death. Median lifespan was significantly extended from 126 days to >259 days when chronic IT treatment was initiated before the onset of disease...
March 17, 2017: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/28335910/management-strategies-for-cln2-disease
#11
REVIEW
Ruth E Williams, Heather R Adams, Martin Blohm, Jessica L Cohen-Pfeffer, Emily de Los Reyes, Jonas Denecke, Kristen Drago, Charlie Fairhurst, Margie Frazier, Norberto Guelbert, Szilárd Kiss, Annamaria Kofler, John A Lawson, Lenora Lehwald, Mary-Anne Leung, Svetlana Mikhaylova, Jonathan W Mink, Miriam Nickel, Renée Shediac, Katherine Sims, Nicola Specchio, Meral Topcu, Ina von Löbbecke, Andrea West, Boris Zernikow, Angela Schulz
CLN2 disease (neuronal ceroid lipofuscinosis type 2) is a rare, autosomal recessive, pediatric-onset, rapidly progressive neurodegenerative lysosomal storage disorder caused by tripeptidyl peptidase 1 (TPP1) enzyme deficiency, and is characterized by language delay, seizures, rapid cognitive and motor decline, blindness, and early death. No management guidelines exist and there is a paucity of published disease-specific evidence to inform clinical practice, which currently draws upon experience from the field of childhood neurodisability...
April 2017: Pediatric Neurology
https://www.readbyqxmd.com/read/28334871/proteomics-insights-into-infantile-neuronal-ceroid-lipofuscinosis-cln1-point-to-the-involvement-of-cilia-pathology-in-the-disease
#12
Michal Segal-Salto, Karin Hansson, Tamar Sapir, Anna Kaplan, Talia Levy, Michaela Schweizer, Michael Frotscher, Peter James, Orly Reiner
Mutations in the depalmitoylation enzyme, palmitoyl protein thioesterase (PPT1), result in the early onset neurodegenerative disease known as Infantile Neuronal Ceroid Lipofuscinosis. Here, we provide proteomic evidence suggesting that PPT1 deficiency could be considered as a ciliopathy. Analysis of membrane proteins from brain enriched for acylated proteins from neonate Ppt1 knock out and control mice revealed a list of 88 proteins with differential expression levels. Amongst them, we identified Rab3IP, which regulates ciliogenesis in concert with Rab8 and Rab11...
May 1, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28239331/csp%C3%AE-a-molecular-co-chaperone-essential-for-short-and-long-term-synaptic-maintenance
#13
Elena Lopez-Ortega, Rocío Ruiz, Lucia Tabares
Cysteine string protein α (CSPα) is a vesicle protein located in the presynaptic terminal of most synapses. CSPα is an essential molecular co-chaperone that facilitates the correct folding of proteins and the assembly of the exocytic machinery. The absence of this protein leads to altered neurotransmitter release and neurodegeneration in multiple model systems, from flies to mice. In humans, CSPα mutations are associated with the development of neuronal ceroid lipofuscinosis (NCL), a neurodegenerative disease characterized by intracellular accumulation of lysosomal material...
2017: Frontiers in Neuroscience
https://www.readbyqxmd.com/read/28213849/widespread-expression-of-a-membrane-tethered-version-of-the-soluble-lysosomal-enzyme-palmitoyl-protein-thioesterase-1
#14
Charles Shyng, Shannon L Macauley, Joshua T Dearborn, Mark S Sands
"Cross-correction," the transfer of soluble lysosomal enzymes between neighboring cells, forms the foundation for therapeutics of lysosomal storage disorders (LSDs). However, "cross-correction" poses a significant barrier to studying the role of specific cell types in LSD pathogenesis. By expressing the native enzyme in only one cell type, neighboring cell types are invariably corrected. In this study, we present a strategy to limit "cross-correction" of palmitoyl-protein thioesterase-1(PPT1), a lysosomal hydrolase deficient in Infantile Neuronal Ceroid Lipofuscinosis (INCL, Infantile Batten disease) to the lysosomal membrane via the C-terminus of lysosomal associated membrane protein-1 (LAMP1)...
February 18, 2017: JIMD Reports
https://www.readbyqxmd.com/read/28199020/gemfibrozil-food-and-drug-administration-approved-lipid-lowering-drug-increases-longevity-in-mouse-model-of-late-infantile-neuronal-ceroid-lipofuscinosis
#15
Arunava Ghosh, Suresh Babu Rangasamy, Khushbu K Modi, Kalipada Pahan
Late Infantile Neuronal Ceroid Lipofuscinosis (LINCL) is a rare neurodegenerative disease caused by mutations in the Cln2 gene that leads to deficiency or loss of function of the tripeptidyl peptidase 1 (TPP1) enzyme. TPP1 deficiency is known to cause the accumulation of autofluoroscent lipid-protein pigments in brain. Similar to other neurodegenerative disorders, LINCL is also associated with neuroinflammation and neuronal damage. Despite investigations, no effective therapy is currently available for LINCL...
May 2017: Journal of Neurochemistry
https://www.readbyqxmd.com/read/28137957/loss-of-function-mutations-in-the-atp13a2-park9-gene-cause-complicated-hereditary-spastic-paraplegia-spg78
#16
Alejandro Estrada-Cuzcano, Shaun Martin, Teodora Chamova, Matthis Synofzik, Dagmar Timmann, Tine Holemans, Albena Andreeva, Jennifer Reichbauer, Riet De Rycke, Dae-In Chang, Sarah van Veen, Jean Samuel, Ludger Schöls, Thorsten Pöppel, Danny Mollerup Sørensen, Bob Asselbergh, Christine Klein, Stephan Zuchner, Albena Jordanova, Peter Vangheluwe, Ivailo Tournev, Rebecca Schüle
Hereditary spastic paraplegias are heterogeneous neurodegenerative disorders characterized by progressive spasticity of the lower limbs due to degeneration of the corticospinal motor neurons. In a Bulgarian family with three siblings affected by complicated hereditary spastic paraplegia, we performed whole exome sequencing and homozygosity mapping and identified a homozygous p.Thr512Ile (c.1535C > T) mutation in ATP13A2. Molecular defects in this gene have been causally associated with Kufor-Rakeb syndrome (#606693), an autosomal recessive form of juvenile-onset parkinsonism, and neuronal ceroid lipofuscinosis (#606693), a neurodegenerative disorder characterized by the intracellular accumulation of autofluorescent lipopigments...
February 2017: Brain: a Journal of Neurology
https://www.readbyqxmd.com/read/28127059/a-cluster-of-palmitoylated-cysteines-are-essential-for-aggregation-of-cysteine-string-protein-mutants-that-cause-neuronal-ceroid-lipofuscinosis
#17
Cinta Diez-Ardanuy, Jennifer Greaves, Kevin R Munro, Nicholas C O Tomkinson, Luke H Chamberlain
Autosomal-dominant adult-onset neuronal ceroid lipofuscinosis (ANCL) is caused by mutation of the DNAJC5 gene encoding cysteine string protein alpha (CSPα). The disease-causing mutations, which result in substitution of leucine-115 with an arginine (L115R) or deletion of the neighbouring leucine-116 (∆L116) in the cysteine-string domain cause CSPα to form high molecular weight SDS-resistant aggregates, which are also present in post-mortem brain tissue from patients. Formation and stability of these mutant aggregates is linked to palmitoylation of the cysteine-string domain, however the regions of the mutant proteins that drive aggregation have not been determined...
December 2017: Scientific Reports
https://www.readbyqxmd.com/read/28102781/a-neurodevelopmental-disorder-with-a-nonsense-mutation-in-the-ox-2-antigen-domain-of-the-amyloid-precursor-protein-app-gene
#18
Khue Vu Nguyen, Karen Leydiker, Raymond Wang, Jose Abdenur, William L Nyhan
We report a patient, an infant with a neurodevelopmental disorder manifesting intractable complex partial epilepsy, bull's eye maculopathy, microcephaly, bilateral cataracts, truncal hypotonia, and spasticity of all four extremities. Sequencing of genomic DNA revealed mutations in (a) exon 8 (Ox-2 antigen domain) of the amyloid precursor protein (APP) gene: c.1075C>T, p.Arg359(*) (b) exon 8 of the senataxin (SETX) gene: c.4738C>T, p.Arg1580Cys, and (c) exon 2 of the ceroid-lipofuscinosis, neuronal 8 (CLN8) gene: c...
May 4, 2017: Nucleosides, Nucleotides & Nucleic Acids
https://www.readbyqxmd.com/read/28079862/extraneuronal-pathology-in-a-canine-model-of-cln2-neuronal-ceroid-lipofuscinosis-after-intracerebroventricular-gene-therapy-that-delays-neurological-disease-progression
#19
M L Katz, G C Johnson, S B Leach, B G Williamson, J R Coates, R E H Whiting, D P Vansteenkiste, M S Whitney
CLN2 neuronal ceroid lipofuscinosis is a hereditary lysosomal storage disease with primarily neurological signs that results from mutations in TPP1, which encodes the lysosomal enzyme tripeptidyl peptidase-1 (TPP1). Studies using a canine model for this disorder demonstrated that delivery of TPP1 enzyme to the cerebrospinal fluid (CSF) by intracerebroventricular administration of an AAV-TPP1 vector resulted in substantial delays in the onset and progression of neurological signs and prolongation of life span...
April 2017: Gene Therapy
https://www.readbyqxmd.com/read/28073925/progranulin-regulates-lysosomal-function-and-biogenesis-through-acidification-of-lysosomes
#20
Yoshinori Tanaka, Genjiro Suzuki, Takashi Matsuwaki, Masato Hosokawa, Geidy Serrano, Thomas G Beach, Keitaro Yamanouchi, Masato Hasegawa, Masugi Nishihara
Progranulin (PGRN) haploinsufficiency resulting from loss-of-function mutations in the PGRN gene causes frontotemporal lobar degeneration accompanied by TDP-43 accumulation, and patients with homozygous mutations in the PGRN gene present with neuronal ceroid lipofuscinosis. Although it remains unknown why PGRN deficiency causes neurodegenerative diseases, there is increasing evidence that PGRN is implicated in lysosomal functions. Here, we show PGRN is a secretory lysosomal protein that regulates lysosomal function and biogenesis by controlling the acidification of lysosomes...
March 1, 2017: Human Molecular Genetics
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