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Your search keyword '"Huebecker, Mylene"' showing total 23 results
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23 results on '"Huebecker, Mylene"'

1. Glb1 knockout mouse model shares natural history with type II GM1 gangliosidosis patients

Author

Nicoli, Elena-Raluca, Huebecker, Mylene, Han, Sangwoo T., Garcia, Karolyn, Munasinghe, Jeeva, Lizak, Martin, Latour, Yvonne, Yoon, Robin, Glase, Brianna, Tyrlik, Michal, Peiravi, Morteza, Springer, Danielle, Baker, Eva H., Priestman, David, Sidhu, Rohini, Kell, Pamela, Jiang, Xuntian, Kolstad, Josephine, Kuhn, Anna Luisa, Shazeeb, Mohammed Salman, Acosta, Maria T., Proia, Richard L., Platt, Frances M., and Tifft, Cynthia J.

Published
2023
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2. Lysosomal dysfunction and glycosphingolipid dysregulation in rare and common neurodegenerative diseases

Author

Huebecker, Mylene and Platt, Frances

Subjects
616.8, Biochemistry, Molecular biology
Abstract

Historically, the rare early-onset neurodegenerative lysosomal storage disorders (LSDs) have been studied as discrete metabolic diseases in their own right. However, in recent years links with more common late-onset neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD), have emerged. For example, lysosomal dysfunction, impaired autophagy, and protein aggregation are shared features in these diseases. However, altered lipid homeostasis, especially glycosphingolipid (GSL) dysregulation, is a relatively new research field of interest in PD and even more so in ALS. In this thesis, we provide evidence that GSL metabolism is altered during denervation, in an ALS mouse model, and in ALS patients. We further show that pharmacological modulation of GSL levels, especially the ganglioside GM1a, could be a therapeutic approach for ALS. Mutations in the Gaucher disease-linked lysosomal enzyme GBA are major genetic risk factors for developing PD. In this thesis, we observed that a subset of sporadic PD fibroblasts phenocopied characteristics of lysosomal dysfunction associated with GBA mutations. Furthermore, ageing is the major non-genetic risk factor for adult-onset neurodegenerative diseases. We show that levels of GSLs and activities of lysosomal hydrolases, relevant to PD, are altered in the ageing brain of wildtype mice. Importantly, we demonstrate, in human post-mortem substantia nigra and putamen, that levels of GSLs, especially complex gangliosides such as GM1a, and multiple lysosomal hydrolase activities are reduced during ageing and to a greater extent in sporadic PD. However, these changes were not observed in mouse models of PD, questioning their usefulness as models for PD. Finally, we demonstrate that ganglioside levels in cerebrospinal fluid and serum from PD patients are potential biomarkers for PD. Consequently, existing LSD therapies may hold promise as new therapeutic approaches for treating PD.

Published
2019

5. Fetal gene therapy for neurodegenerative disease of infants

Author

Massaro, Giulia, Mattar, Citra N. Z., Wong, Andrew M. S., Sirka, Ernestas, Buckley, Suzanne M. K., Herbert, Bronwen R., Karlsson, Stefan, Perocheau, Dany P., Burke, Derek, Heales, Simon, Richard-Londt, Angela, Brandner, Sebastian, Huebecker, Mylene, Priestman, David A., Platt, Frances M., Mills, Kevin, Biswas, Arijit, Cooper, Jonathan D., Chan, Jerry K. Y., Cheng, Seng H., Waddington, Simon N., and Rahim, Ahad A.

Published
2018
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10. Amyotrophic lateral sclerosis and denervation alter sphingolipids and up-regulate glucosylceramide synthase

Author

Henriques, Alexandre, Croixmarie, Vincent, Priestman, David A., Rosenbohm, Angela, Dirrig-Grosch, Sylvie, DʼAmbra, Eleonora, Huebecker, Mylene, Hussain, Ghulam, Boursier-Neyret, Claire, Echaniz-Laguna, Andoni, Ludolph, Albert C., Platt, Frances M., Walther, Bernard, Spedding, Michael, Loeffler, Jean-Philippe, and Gonzalez De Aguilar, Jose-Luis

Published
2015
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11. Upregulating β-hexosaminidase activity in rodents prevents α-synuclein lipid associations and protects dopaminergic neurons from α-synuclein-mediated neurotoxicity

Author

Brekk, Oeystein R., primary, Korecka, Joanna A., additional, Crapart, Cecile C., additional, Huebecker, Mylene, additional, MacBain, Zachary K., additional, Rosenthal, Sara Ann, additional, Sena-Esteves, Miguel, additional, Priestman, David A., additional, Platt, Frances M., additional, Isacson, Ole, additional, and Hallett, Penelope J., additional

Published
2020
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13. Targeting GLB1 in mice by CRISPR/Cas9 genome editing: Establishing a novel model for type II GM1 gangliosidosis

Author

Nicoli, Elena-Raluca, primary, Han, Ted, additional, Yoon, Robin, additional, Glase, Brianna, additional, Latour, Yvonne, additional, Huebecker, Mylene, additional, D'Souza, Andrea, additional, Peiravi, Morteza, additional, Tyrlik, Michal, additional, Springer, Danielle, additional, Jeeva, Jeeva Munasinghe, additional, Donahue, Danielle, additional, Sidhu, Rohini, additional, Kell, Pamela, additional, Jiang, Xuntian, additional, Acosta, Maria, additional, Platt, Frances M., additional, Proia, Richard L., additional, and Tifft, Cynthia J., additional

Published
2020
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14. Genetic background modifies phenotypic severity and longevity in a mouse model of Niemann-Pick disease type C1

Author

Rodriguez-Gil, Jorge L., primary, Watkins-Chow, Dawn E., additional, Baxter, Laura L., additional, Elliot, Gene, additional, Harper, Ursula L., additional, Wincovitch, Stephen M., additional, Wedel, Julia C., additional, Incao, Arturo A., additional, Huebecker, Mylene, additional, Boehm, Frederick J., additional, Garver, William S., additional, Porter, Forbes D., additional, Broman, Karl W., additional, Platt, Frances M., additional, and Pavan, William J., additional

Published
2020
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15. 2‐Sulfonylpyrimidines Target the Kinesin HSET via Cysteine Alkylation

Author

Förster, Tim, primary, Shang, Erchang, additional, Shimizu, Kenshiro, additional, Sanada, Emiko, additional, Schölermann, Beate, additional, Huebecker, Mylene, additional, Hahne, Gernot, additional, López‐Alberca, Maria Pascual, additional, Janning, Petra, additional, Watanabe, Nobumoto, additional, Sievers, Sonja, additional, Giordanetto, Fabrizio, additional, Shimizu, Takeshi, additional, Ziegler, Slava, additional, Osada, Hiroyuki, additional, and Waldmann, Herbert, additional

Published
2019
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16. AAV9 intracerebroventricular gene therapy improves lifespan, locomotor function and pathology in a mouse model of Niemann–Pick type C1 disease

Author

Hughes, Michael P, primary, Smith, Dave A, additional, Morris, Lauren, additional, Fletcher, Claire, additional, Colaco, Alexandria, additional, Huebecker, Mylene, additional, Tordo, Julie, additional, Palomar, Nuria, additional, Massaro, Giulia, additional, Henckaerts, Els, additional, Waddington, Simon N, additional, Platt, Frances M, additional, and Rahim, Ahad A, additional

Published
2018
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18. Altered Expression of Ganglioside Metabolizing Enzymes Results in GM3 Ganglioside Accumulation in Cerebellar Cells of a Mouse Model of Juvenile Neuronal Ceroid Lipofuscinosis

Author

Somogyi, Aleksandra, primary, Petcherski, Anton, additional, Beckert, Benedikt, additional, Huebecker, Mylene, additional, Priestman, David, additional, Banning, Antje, additional, Cotman, Susan, additional, Platt, Frances, additional, Ruonala, Mika, additional, and Tikkanen, Ritva, additional

Published
2018
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19. Inhibition of β-Glucocerebrosidase Activity Preserves Motor Unit Integrity in a Mouse Model of Amyotrophic Lateral Sclerosis

Author

Henriques, Alexandre, Huebecker, Mylene, Blasco, Hélène, Keime, Céline, Andres, Christian, Corcia, Philippe, Priestman, David, Platt, Frances, Spedding, Michael, Loeffler, Jean-Philippe, Dieterle, Stéphane, Mécanismes Centraux et Périphériques de la Neurodégénérescence, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Spedding Research Solutions SAS [Le Vesinet, France], University of Oxford, Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of Oxford [Oxford], Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), and Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS)

Subjects
Male, MESH: Signal Transduction, MESH: Rats, Science, [SDV]Life Sciences [q-bio], Neuromuscular Junction, MESH: Glucosylceramidase, PC12 Cells, MESH: Mice, Knockout, Article, Glycosphingolipids, MESH: Spinal Cord, Mice, [SCCO]Cognitive science, Animals, Humans, MESH: PC12 Cells, MESH: Animals, MESH: Mice, MESH: Amyotrophic Lateral Sclerosis, MESH: Superoxide Dismutase, Aged, Mice, Knockout, Motor Neurons, MESH: Aged, MESH: Humans, Superoxide Dismutase, Amyotrophic Lateral Sclerosis, MESH: Glycosphingolipids, [SCCO] Cognitive science, MESH: Case-Control Studies, MESH: Male, Rats, [SDV] Life Sciences [q-bio], Disease Models, Animal, Spinal Cord, Case-Control Studies, Glucosylceramidase, Medicine, Female, MESH: Neuromuscular Junction, MESH: Disease Models, Animal, MESH: Female, MESH: Motor Neurons, Signal Transduction
Abstract

International audience; Recent metabolomic reports connect dysregulation of glycosphingolipids, particularly ceramide and glucosylceramide, to neurodegeneration and to motor unit dismantling in amyotrophic lateral sclerosis at late disease stage. We report here altered levels of gangliosides in the cerebrospinal fluid of amyotrophic lateral sclerosis patients in early disease stage. Conduritol B epoxide is an inhibitor of acid beta-glucosidase, and lowers glucosylceramide degradation. Glucosylceramide is the precursor for all of the more complex glycosphingolipids. In SOD1G86R mice, an animal model of amyotrophic lateral sclerosis, conduritol B epoxide preserved ganglioside distribution at the neuromuscular junction, delayed disease onset, improved motor function and preserved motor neurons as well as neuromuscular junctions from degeneration. Conduritol B epoxide mitigated gene dysregulation in the spinal cord and restored the expression of genes involved in signal transduction and axonal elongation. Inhibition of acid beta-glucosidase promoted faster axonal elongation in an in vitro model of neuromuscular junctions and hastened recovery after peripheral nerve injury in wild type mice. Here, we provide evidence that glycosphingolipids play an important role in muscle innervation, which degenerates in amyotrophic lateral sclerosis from the early disease stage. This is a first proof of concept study showing that modulating the catabolism of glucosylceramide may be a therapeutic target for this devastating disease.

Published
2017
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20. N-Butyl-l-deoxynojirimycin (l-NBDNJ): Synthesis of an Allosteric Enhancer of α-Glucosidase Activity for the Treatment of Pompe Disease

Author

D’Alonzo, Daniele, primary, De Fenza, Maria, additional, Porto, Caterina, additional, Iacono, Roberta, additional, Huebecker, Mylene, additional, Cobucci-Ponzano, Beatrice, additional, Priestman, David A., additional, Platt, Frances, additional, Parenti, Giancarlo, additional, Moracci, Marco, additional, Palumbo, Giovanni, additional, and Guaragna, Annalisa, additional

Published
2017
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22. Differential response of the liver to bile acid treatment in a mouse model of Niemann-Pick disease type C.

Author

Nicoli ER, Huebecker M, Smith D, Morris L, and Platt FM

Abstract

Niemann-Pick disease type C (NPC) disease is a neurodegenerative lysosomal storage disease caused by mutations in the NPC1 or NPC2 genes. Liver disease is also a common feature of NPC that can present as cholestatic jaundice in the neonatal period. Liver enzymes can remain elevated above the normal range in some patients as they age. We recently reported suppression of the P450 detoxification system in a mouse model of NPC disease and in post-mortem liver from NPC patients. As bile acids regulate the P450 system, we tested bile acid treatment using ursodeoxycholic acid (UDCA; 3α, 7β-dihydroxy-5β-cholanic acid), a hydrophilic bile acid, which is used to treat several cholestatic disorders. In this study, we compared UDCA treatment with the bile acid cholic acid (CA), and found unexpected hepatotoxicity in response to CA in Npc1 mice, but not to UDCA, suggesting that only UDCA should be used as an adjunctive therapy in NPC patients., Competing Interests: Competing interests: FP is a co-founder and consultant to IntraBio.

Published
2017
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23. Inhibition of β-Glucocerebrosidase Activity Preserves Motor Unit Integrity in a Mouse Model of Amyotrophic Lateral Sclerosis.

Author

Henriques A, Huebecker M, Blasco H, Keime C, Andres CR, Corcia P, Priestman DA, Platt FM, Spedding M, and Loeffler JP

Subjects
Aged, Animals, Case-Control Studies, Female, Humans, Male, Mice, Mice, Knockout, Neuromuscular Junction physiology, PC12 Cells, Rats, Signal Transduction, Amyotrophic Lateral Sclerosis physiopathology, Disease Models, Animal, Glucosylceramidase antagonists & inhibitors, Glycosphingolipids metabolism, Motor Neurons physiology, Spinal Cord physiology, Superoxide Dismutase physiology
Abstract

Recent metabolomic reports connect dysregulation of glycosphingolipids, particularly ceramide and glucosylceramide, to neurodegeneration and to motor unit dismantling in amyotrophic lateral sclerosis at late disease stage. We report here altered levels of gangliosides in the cerebrospinal fluid of amyotrophic lateral sclerosis patients in early disease stage. Conduritol B epoxide is an inhibitor of acid beta-glucosidase, and lowers glucosylceramide degradation. Glucosylceramide is the precursor for all of the more complex glycosphingolipids. In SOD1 G86R mice, an animal model of amyotrophic lateral sclerosis, conduritol B epoxide preserved ganglioside distribution at the neuromuscular junction, delayed disease onset, improved motor function and preserved motor neurons as well as neuromuscular junctions from degeneration. Conduritol B epoxide mitigated gene dysregulation in the spinal cord and restored the expression of genes involved in signal transduction and axonal elongation. Inhibition of acid beta-glucosidase promoted faster axonal elongation in an in vitro model of neuromuscular junctions and hastened recovery after peripheral nerve injury in wild type mice. Here, we provide evidence that glycosphingolipids play an important role in muscle innervation, which degenerates in amyotrophic lateral sclerosis from the early disease stage. This is a first proof of concept study showing that modulating the catabolism of glucosylceramide may be a therapeutic target for this devastating disease.

Published
2017
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