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https://www.readbyqxmd.com/read/28673981/synergistic-effects-of-treating-the-spinal-cord-and-brain-in-cln1-disease
#1
Charles Shyng, Hemanth R Nelvagal, Joshua T Dearborn, Jaana Tyynelä, Robert E Schmidt, Mark S Sands, Jonathan D Cooper
Infantile neuronal ceroid lipofuscinosis (INCL, or CLN1 disease) is an inherited neurodegenerative storage disorder caused by a deficiency of the lysosomal enzyme palmitoyl protein thioesterase 1 (PPT1). It was widely believed that the pathology associated with INCL was limited to the brain, but we have now found unexpectedly profound pathology in the human INCL spinal cord. Similar pathological changes also occur at every level of the spinal cord of PPT1-deficient (Ppt1(-/-) ) mice before the onset of neuropathology in the brain...
July 3, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28647554/conditional-loss-of-progranulin-in-neurons-is-not-sufficient-to-cause-neuronal-ceroid-lipofuscinosis-like-neuropathology-in-mice
#2
Terri L Petkau, Jake Blanco, Blair R Leavitt
Progranulin deficiency due to heterozygous null mutations in the GRN gene is a common cause of familial frontotemporal lobar degeneration (FTLD), while homozygous loss-of-function GRN mutations cause neuronal ceroid lipofuscinosis (NCL). Aged progranulin-knockout mice display highly exaggerated lipofuscinosis, microgliosis, and astrogliosis, as well as mild cell loss in specific brain regions. Progranulin is a secreted glycoprotein expressed in both neurons and microglia, but not astrocytes, in the brain. We generated conditional progranulin-knockout mice that lack progranulin in nestin-expressing cells (Nes-cKO mice), which include most neurons as well as astrocytes...
June 21, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/28632327/photosensitivity-is-an-early-marker-of-neuronal-ceroid-lipofuscinosis-type-2-disease
#3
Nicola Specchio, Marcello Bellusci, Nicola Pietrafusa, Marina Trivisano, Luca de Palma, Federico Vigevano
OBJECTIVE: This study aimed to identify early clinical, magnetic resonance imaging (MRI), and electroencephalographic (EEG) characteristics of neuronal ceroid lipofuscinosis type 2 (CLN2) disease to enable early diagnosis, thus providing the key to early treatment, and optimized care and outcomes. METHODS: Retrospective clinical chart review of a series of patients diagnosed with CLN2 disease from 2005 to 2015 at a single center in Italy. Clinical, MRI, and EEG findings were reviewed...
June 20, 2017: Epilepsia
https://www.readbyqxmd.com/read/28623936/safety-and-potential-efficacy-of-gemfibrozil-as-a-supportive-treatment-for-children-with-late-infantile-neuronal-ceroid-lipofuscinosis-and-other-lipid-storage-disorders
#4
REVIEW
Kyeongsoon Kim, Hynda K Kleinman, Hahn-Jun Lee, Kalipada Pahan
Neuronal Ceroid Lipofuscinosis (NCL), also known as Batten disease, is a group of genetically distinct lysosomal disorders that mainly affect the central nervous system, resulting in progressive motor and cognitive decline primarily in children. Multiple distinct genes involved in the metabolism of lipids have been identified to date with various mutations in this family of diseases. There is no cure for these diseases but some new therapeutic approaches have been tested that offer more hope than the standard palliative care...
June 17, 2017: Orphanet Journal of Rare Diseases
https://www.readbyqxmd.com/read/28595912/the-effect-of-manganese-exposure-in-atp13a2-deficient-mice
#5
Sheila M Fleming, Nicholas A Santiago, Elizabeth J Mullin, Shanta Pamphile, Swagata Karkare, Andrew Lemkuhl, Osunde R Ekhator, Stephen C Linn, John G Holden, Diana S Aga, Jerome A Roth, Benjamin Liou, Ying Sun, Gary E Shull, Patrick J Schultheis
Loss of function mutations in the P5-ATPase ATP13A2 are associated with Kufor-Rakeb Syndrome and Neuronal Ceroid Lipofuscinosis. While the function of ATP13A2 is unclear, in vitro studies suggest it is a lysosomal protein that interacts with the metals manganese (Mn) and zinc and the presynaptic protein alpha-synuclein. Loss of ATP13A2 function in mice causes sensorimotor deficits, enhanced autofluorescent storage material, and accumulation of alpha-synuclein. The present study sought to determine the effect of Mn administration on these same outcomes in ATP13A2-deficient mice...
June 6, 2017: Neurotoxicology
https://www.readbyqxmd.com/read/28589525/cerliponase-alfa-first-global-approval
#6
Anthony Markham
Cerliponase alfa (Brineura™) is a recombinant human tripeptidyl peptidase-1 (TPP1) being developed by BioMarin Pharmaceutical Inc. for use in patients with neuronal ceroid lipofuscinosis type 2 (CLN2), a paediatric neurodegenerative disease caused by a deficiency in TPP1. CLN2 is characterised by progressive impairment of motor function, language deficiencies, seizures, ataxia, blindness and early death, and intracerebroventricular infusion of cerliponase alfa has been shown to reduce the progression of functional decline...
July 2017: Drugs
https://www.readbyqxmd.com/read/28587997/long-term-follow-up-of-two-siblings-with-adult-onset-neuronal-ceroid-lipofuscinosis-kufs-type-a
#7
Çiğdem Özkara, Ayşegül Gündüz, Tülin Coşkun, Bengi Gül Alpaslan, Burcu Zeydan, Şakir Delil, Mikko Muona, Anna-Elina Lehesjoki, Meral E Kızıltan
Reports on the clinical presentation of adult-onset neuronal ceroid lipofuscinoses (NCL) are scarce compared to infantile- and childhood-onset forms. Here, we aimed to present detailed temporal evolution of clinical and electrophysiological features of two siblings with adult-onset NCL and homozygous mutation in the CLN6 gene. We retrospectively analysed medical records and electrophysiological data in order to delineate evolution of clinical and electrophysiological findings. Electrophysiological studies included routine EEG and video-EEG, as well as polymyographic analysis of myoclonus and brainstem reflex studies...
June 6, 2017: Epileptic Disorders: International Epilepsy Journal with Videotape
https://www.readbyqxmd.com/read/28586915/specific-alleles-of-cln7-mfsd8-a-protein-that-localizes-to-photoreceptor-synaptic-terminals-cause-a-spectrum-of-nonsyndromic-retinal-dystrophy
#8
MULTICENTER STUDY
Kamron N Khan, Mohammed E El-Asrag, Cristy A Ku, Graham E Holder, Martin McKibbin, Gavin Arno, James A Poulter, Keren Carss, Tejaswi Bommireddy, Saghar Bagheri, Benjamin Bakall, Hendrik P Scholl, F Lucy Raymond, Carmel Toomes, Chris F Inglehearn, Mark E Pennesi, Anthony T Moore, Michel Michaelides, Andrew R Webster, Manir Ali
Purpose: Recessive mutations in CLN7/MFSD8 usually cause variant late-infantile onset neuronal ceroid lipofuscinosis (vLINCL), a poorly understood neurodegenerative condition, though mutations may also cause nonsyndromic maculopathy. A series of 12 patients with nonsyndromic retinopathy due to novel CLN7/MFSD8 mutation combinations were investigated in this study. Methods: Affected patients and their family members were recruited in ophthalmic clinics at each center where they were examined by retinal imaging and detailed electrophysiology...
June 1, 2017: Investigative Ophthalmology & Visual Science
https://www.readbyqxmd.com/read/28579939/the-role-of-co-chaperones-in-synaptic-proteostasis-and-neurodegenerative-disease
#9
REVIEW
Erica L Gorenberg, Sreeganga S Chandra
Synapses must be preserved throughout an organism's lifespan to allow for normal brain function and behavior. Synapse maintenance is challenging given the long distances between the termini and the cell body, reliance on axonal transport for delivery of newly synthesized presynaptic proteins, and high rates of synaptic vesicle exo- and endocytosis. Hence, synapses rely on efficient proteostasis mechanisms to preserve their structure and function. To this end, the synaptic compartment has specific chaperones to support its functions...
2017: Frontiers in Neuroscience
https://www.readbyqxmd.com/read/28546289/a-tripeptidyl-peptidase-1-is-a-binding-partner-of-gphr-golgi-ph-regulator-in-dictyostelium
#10
Maria Stumpf, Rolf Müller, Berthold Gaßen, Regina Wehrstedt, Petra Fey, Malte A Karow, Ludwig Eichinger, Gernot Glöckner, Angelika A Noegel
Mutations in tripeptidyl peptidase 1 (TPP1) have been associated with late infantile neuronal ceroid lipofuscinosis (NCL2), a neurodegenerative disorder. TPP1 is a lysosomal serine protease, which removes tripeptides from the amino terminus of proteins and is composed of an N-terminal prodomain and a catalytic domain. It is conserved in mammals, amphibians, fish and the amoeba Dictyostelium discoideum. D. discoideum harbors at least six genes encoding tripeptidyl peptidase 1, tpp1A to tpp1F We identified TPP1F as binding partner of Dictyostelium GPHR (Golgi pH regulator), which is an evolutionary highly conserved intracellular transmembrane protein...
May 25, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28542837/phenotype-and-natural-history-of-variant-late-infantile-ceroid-lipofuscinosis-5
#11
MULTICENTER STUDY
Alessandro Simonati, Ruth E Williams, Nardo Nardocci, Minna Laine, Roberta Battini, Angela Schulz, Barbara Garavaglia, Francesca Moro, Francesco Pezzini, Filippo M Santorelli
AIM: To characterize the phenotypic profile of a cohort of children affected with CLN5, a rare form of neuronal ceroid-lipofuscinosis (NCL), and to trace the features of the natural history of the disease. METHOD: Records of 15 children (nine males, six females) were obtained from the data sets of the DEM-CHILD International NCL Registry. Disease progression was measured by rating six functional domains at different time points along the disease course. All patients underwent mutation analysis of the CLN5 gene and ultrastructural investigations of peripheral tissues...
August 2017: Developmental Medicine and Child Neurology
https://www.readbyqxmd.com/read/28542676/detailed-clinical-phenotype-and-molecular-genetic-findings-in-cln3-associated-isolated-retinal-degeneration
#12
Cristy A Ku, Sarah Hull, Gavin Arno, Ajoy Vincent, Keren Carss, Robert Kayton, Douglas Weeks, Glenn W Anderson, Ryan Geraets, Camille Parker, David A Pearce, Michel Michaelides, Robert E MacLaren, Anthony G Robson, Graham E Holder, Elise Heon, F Lucy Raymond, Anthony T Moore, Andrew R Webster, Mark E Pennesi
Importance: Mutations in genes traditionally associated with syndromic retinal disease are increasingly found to cause nonsyndromic inherited retinal degenerations. Mutations in CLN3 are classically associated with juvenile neuronal ceroid lipofuscinosis, a rare neurodegenerative disease with early retinal degeneration and progressive neurologic deterioration, but have recently also been identified in patients with nonsyndromic inherited retinal degenerations. To our knowledge, detailed clinical characterization of such cases has yet to be reported...
July 1, 2017: JAMA Ophthalmology
https://www.readbyqxmd.com/read/28541286/impaired-prosaposin-lysosomal-trafficking-in-frontotemporal-lobar-degeneration-due-to-progranulin-mutations
#13
Xiaolai Zhou, Lirong Sun, Oliver Bracko, Ji Whae Choi, Yan Jia, Alissa L Nana, Owen Adam Brady, Jean C Cruz Hernandez, Nozomi Nishimura, William W Seeley, Fenghua Hu
Haploinsufficiency of progranulin (PGRN) due to mutations in the granulin (GRN) gene causes frontotemporal lobar degeneration (FTLD), and complete loss of PGRN leads to a lysosomal storage disorder, neuronal ceroid lipofuscinosis (NCL). Accumulating evidence suggests that PGRN is essential for proper lysosomal function, but the precise mechanisms involved are not known. Here, we show that PGRN facilitates neuronal uptake and lysosomal delivery of prosaposin (PSAP), the precursor of saposin peptides that are essential for lysosomal glycosphingolipid degradation...
May 25, 2017: Nature Communications
https://www.readbyqxmd.com/read/28506594/fingolimod-and-teriflunomide-attenuate-neurodegeneration-in-mouse-models-of-neuronal-ceroid-lipofuscinosis
#14
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
#15
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
#16
Xiaomin Yao, Xiaowei Liu, Yaguang Zhang, Yuhao Li, Chenjian Zhao, Shaohua Yao, Yuquan 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 the DNAJC5 gene that encodes cysteine-string protein alpha (CSPα) have been reported to be associated with familial autosomal-dominant ANCL (AD-ANCL). This study constructed an ANCL transgenic zebrafish model expressing the human mutant DNAJC5 (mDNAJC5) gene under the control of a zebrafish neuron-specific promoter...
July 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
#17
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
#18
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...
July 5, 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
#19
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 characterized for tripeptidyl peptidase 1 (TPP1), α-N-acetylglucosaminidase (NAGLU), and lysosomal β-glucuronidase (GUSB)...
June 2017: Clinical Chemistry
https://www.readbyqxmd.com/read/28404863/individuals-with-progranulin-haploinsufficiency-exhibit-features-of-neuronal-ceroid-lipofuscinosis
#20
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
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