Article
Biochemistry & Molecular Biology
Oluwanifemi Shola-Dare, Shelby Bailess, Carlos C. Flores, William M. Vanderheyden, Jason R. Gerstner
Summary: Parkinson's Disease (PD) and Gaucher Disease (GD) are genetically linked, with no effective treatment currently available. Research has shown that thiazolidinediones may help improve the neurological symptoms of these two diseases. By enhancing the function of the lysosomal-autophagy pathways, these compounds could enhance the treatment outcomes of both diseases.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Cell Biology
Yanyan Peng, Benjamin Liou, Yi Lin, Venette Fannin, Wujuan Zhang, Ricardo A. Feldman, Kenneth D. R. Setchell, Gregory A. Grabowski, Ying Sun
Summary: This study demonstrates that substrate reduction therapy can effectively ameliorate substrate accumulation in neurons of patients with Gaucher disease, reduce enlarged lysosomes and autophagic vacuoles, improve mitochondrial function, decrease hyperactivity of proteins in the mTORC1 pathway, and enhance cell proliferation. These findings suggest mitochondria and the mTORC1 complex as potential therapeutic targets for the treatment of Gaucher disease.
Review
Neurosciences
Yael Pewzner-Jung, Tammar Joseph, Shani Blumenreich, Ayelet Vardi, Natalia Santos Ferreira, Soo Min Cho, Raya Eilam, Michael Tsoory, Inbal E. Biton, Vlad Brumfeld, Rebecca Haffner-Krausz, Ori Brenner, Nir Sharabi, Yoseph Addadi, Tomer-Meir Salame, Ron Rotkopf, Noa Wigoda, Nadav Yayon, Alfred H. Merrill, Raphael Schiffmann, Anthony H. Futerman
Summary: The study presents a mouse model that phenotypically resembles chronic neuronopathic type 3 GD, showing behavioral abnormalities and significant neuropathology similar to acute GD models but with some differences. This model may help in understanding the distinct disease progression of type 2 and 3 patients.
PROGRESS IN NEUROBIOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Takahiro Fujii, Yuta Tanaka, Hideyuki Oki, Sho Sato, Sachio Shibata, Takamitsu Maru, Yuta Tanaka, Maiko Tanaka, Tomohiro Onishi
Summary: Gaucher disease, caused by mutations in the GBA gene, results in the accumulation of glycosphingolipids in tissues such as the brain. Current treatments focus on suppressing glycosphingolipid accumulation in peripheral symptoms, but there is a lack of effective treatment for central nervous system symptoms. A new study identified T-036 as a promising brain-penetrant GCS inhibitor with unique chemical properties, showing significant reduction in glucosylsphingolipids in a GD mouse model.
JOURNAL OF NEUROCHEMISTRY
(2021)
Article
Neurosciences
Casey L. Mahoney-Crane, Megha Viswanathan, Dreson Russell, Rachel A. C. Curtiss, Jennifer Freire, Sai Sumedha Bobba, Sean D. Coyle, Monika Kandebo, Lihang Yao, Bang -Lin Wan, Nathan G. Hatcher, Sean M. Smith, Jacob N. Marcus, Laura A. Volpicelli-Daley
Summary: The most common genetic risk factor for Parkinson's disease is heterozygous mutations GBA1, which leads to reduced glucocerebrosidase activity and accumulation of abnormal α-synuclein. This study used GBA1+/L444P mice to investigate its effects on lipid metabolism, synaptic protein expression, behavior, and α-syn inclusion formation.
JOURNAL OF NEUROSCIENCE
(2023)
Article
Clinical Neurology
Jonas M. den Heijer, Valerie C. Cullen, Diana R. Pereira, Yalcin Yavuz, Marieke L. de Kam, Hendrika W. Grievink, Matthijs Moerland, Nancy Leymarie, Kshitij Khatri, Imelda Sollomoni, Leslie Spitalny, Lindsay Dungeon, Dana C. Hilt, Craig Justman, Peter Lansbury, Geert Jan Groeneveld
Summary: This study assessed the variability of various glycosphingolipids (GSLs) in plasma, peripheral blood mononuclear cells (PBMCs), and cerebrospinal fluid (CSF) across GBA-PD, iPD, and HVs. The results showed that plasma levels of glucosylceramide were slightly higher in GBA-PD compared with iPD and HVs, while intracellular levels were comparable. There was no correlation between GSLs in different matrices.
MOVEMENT DISORDERS
(2023)
Article
Clinical Neurology
Jonas M. den Heijer, Valerie C. Cullen, Diana R. Pereira, Yalcin Yavuz, Marieke L. de Kam, Hendrika W. Grievink, Matthijs Moerland, Nancy Leymarie, Kshitij Khatri, Imelda Sollomoni, Leslie Spitalny, Lindsay Dungeon, Dana C. Hilt, Craig Justman, Peter Lansbury, Geert Jan Groeneveld
Summary: This study assessed the variability of various GSLs in plasma, PBMCs, and CSF across GBA-PD, iPD, and HVs. Glucosylceramide was found to be a stable biomarker for GBA-PD clinical trials, while lactosylceramide and glucosylsphingosine were affected by leukocyte subtypes in PBMCs. GBA-PD could be differentiated from iPD and HVs based on glucosylceramide levels in plasma.
MOVEMENT DISORDERS
(2023)
Article
Biochemistry & Molecular Biology
Manoj Kumar, Manasa P. Srikanth, Michela Deleidi, Penelope J. Hallett, Ole Isacson, Ricardo A. Feldman
Summary: Bi-allelic mutations in GBA1 cause Gaucher disease, while mono-allelic mutations are the highest risk factor for Parkinson's disease. In this study, induced pluripotent stem cell-derived dopaminergic neurons with heterozygote GBA1 mutations were used to investigate the mechanisms of GBA1-associated PD. The results showed that GBA1/PD neurons exhibited mTORC1 hyperactivity, autophagy blockage, and increased levels of phosphorylated alpha-synuclein and alpha-synuclein aggregation. These abnormalities were prevented by mTOR inhibitors and inhibition of acid ceramidase. The findings suggest that GluSph is responsible for the alterations and acid ceramidase could be a potential therapeutic target for synucleinopathies caused by GCase deficiency.
HUMAN MOLECULAR GENETICS
(2023)
Article
Biology
Mohsen Basiri, Mohammad E. Ghaffari, Jiapeng Ruan, Vagishwari Murugesan, Nathaniel Kleytman, Glenn Belinsky, Amir Akhavan, Andrew Lischuk, Lilu Guo, Katherine Klinger, Pramod K. Mistry
Summary: In patients with Gaucher disease receiving enzyme replacement therapy or substrate reduction therapy, there is a low but significant risk of avascular osteonecrosis. This risk is associated with GBA genotype, history of previous osteonecrosis, serum GlcSph levels, and the type of therapy received.
Article
Neurosciences
Laetitia Francelle, Joseph R. Mazzulli
Summary: This article reviews the relationship between lysosomal storage diseases (LSDs) and neurodegenerative diseases such as Parkinson's disease (PD), focusing on the role of glial cells and neuroinflammation. The study explains that lysosomal dysfunction and accumulation of storage materials can activate glial cells, but prolonged glial activation may lead to neuron loss. These findings provide new therapeutic approaches for the treatment of PD and LSDs.
Review
Biochemistry & Molecular Biology
Makaila L. Furderer, Ellen Hertz, Grisel J. Lopez, Ellen Sidransky
Summary: Deficiency of acid beta-glucocerebrosidase activity due to mutations in GBA1 causes Gaucher disease (GD). GD patients exhibit a wide range of symptoms, from asymptomatic adults to severe neurodegeneration. GBA1 variants are also important risk factors for several common Lewy body disorders (LBDs). Further neuropathological examinations in GD are needed to understand disease-specific patterns and mechanisms.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Biochemistry & Molecular Biology
Pawel Dubiela, Paulina Szymanska-Rozek, Andrzej Eljaszewicz, Patryk Lipinski, Piotr Hasinski, Dorota Giersz, Alicja Walewska, Marlena Tynecka, Marcin Moniuszko, Anna Tylki-Szymanska
Summary: Gaucher disease, caused by GBA1 gene variants, is characterized by hepatosplenomegaly, hematological abnormalities, and bone disease. GBA1 variants are also important risk factors for Parkinson's disease. A study investigated biomarkers for Gaucher disease and Parkinson's disease in patients receiving enzyme replacement therapy (ERT). The results showed elevated levels of alpha-synuclein mRNA in GD3 patients and L444P carriers, while GD1 patients, GBA1 carriers with unknown variants, and healthy controls had low levels of alpha-synuclein mRNA. The level of alpha-synuclein mRNA did not correlate with age in GD patients treated with ERT, except for L444P carriers.
Review
Genetics & Heredity
Gaetano Giuffrida, Uros Markovic, Annalisa Condorelli, Valeria Calafiore, Daniela Nicolosi, Marianna Calagna, Stephanie Grasso, Marco Tindaro Valentino Ragusa, Jennifer Gentile, Mariasanta Napolitano
Summary: Gaucher disease (GD) is a rare genetic disorder caused by a deficiency of the lysosomal enzyme acid beta-glucosidase. Currently, the most promising biomarker for diagnosing and monitoring GD is glucosylsphingosine (lyso-Gb1), which has high sensitivity and specificity. Lyso-Gb1 can also provide insights into other associated diseases in GD patients.
ORPHANET JOURNAL OF RARE DISEASES
(2023)
Article
Biochemistry & Molecular Biology
Tama Dinur, Peter Bauer, Christian Beetz, Guido Kramp, Claudia Cozma, Marius-Ionut Iurascu, Michal Becker-Cohen, Majdolen Istaiti, Arndt Rolfs, Ari Zimran, Shoshana Revel-Vilk
Summary: This study reviews seven years of experience using dried blood spot (DBS) samples and lyso-Gb1 levels for diagnosing Gaucher disease (GD) and calls for a paradigm change in GD diagnosis based on lyso-Gb1 measurements and GBA1 mutation analyses.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Pharmacology & Pharmacy
Andrea Duminuco, Manlio Fazio, Stephanie Grasso, Lara Gullo, Carla Riccobene, Valeria Calafiore, Uros Markovic, Francesco Di Raimondo, Gaetano Giuffrida
Summary: This study evaluated the effectiveness and safety of eliglustat in Gaucher disease patients and found that it can effectively reduce the levels of chitotriosidase and glucosylsphingosine. The drug showed no serious adverse effects or cardiac events. The study suggests that eliglustat can be a promising treatment option for Gaucher disease patients.
CLINICAL THERAPEUTICS
(2023)
Article
Biochemistry & Molecular Biology
Shani Blumenreich, Chen Yaacobi, Ayelet Vardi, Or B. Barav, Einat B. Vitner, Hyejung Park, Bing Wang, Seng H. Cheng, Sergio P. Sardi, Anthony H. Futerman
Summary: The study showed that SRT is effective in reversing the pathological components and pathways of substrate accumulation in nGD brain by inhibiting the synthesis of glycosphingolipids to reduce their accumulation. This approach can reverse the changes in GSL metabolism, lipoproteins, and other lipid metabolic pathways associated with CBE injection, demonstrating the potential of SRT in treating nGD with a neurological component.
JOURNAL OF NEUROCHEMISTRY
(2021)
Article
Medicine, Research & Experimental
Nasrullah Jan, Asadullah Madni, Muhammad Abdur Rahim, Naveed Ullah Khan, Talha Jamshaid, Arshad Khan, Abdul Jabar, Safiullah Khan, Hassan Shah
Summary: The study aimed to develop and evaluate PCL nanoparticles loaded with cytarabine for sustained release behavior and anti-leukemic influence. The developed nanoparticles showed efficient toxicity against leukemic and breast cancer cell lines, with sustained release pattern enhancing the anti-cancer effects.
Article
Biotechnology & Applied Microbiology
Steffen Schmidt, Sandra F. Gallego, Iris Daphne Zelnik, Sergey Kovalchuk, Nanna Albaek, Richard R. Sprenger, Charlotte Overup, Yael Pewzner-Jung, Anthony H. Futerman, Marie W. Lindholm, Ole N. Jensen, Christer S. Ejsing
Summary: Emerging clinical data show that three ceramide molecules, Cer d18:1/16:0, Cer d18:1/24:1, and Cer d18:1/24:0, are biomarkers of a fatal outcome in patients with cardiovascular disease. This study developed a potent N-acetylgalactosamine-conjugated antisense oligonucleotide that specifically targets ceramide synthase 2 in hepatocytes. Results demonstrate that this compound effectively reduces ceramide synthase 2 mRNA level, leading to lower protein expression and activity as well as ceramide levels in the liver. Interestingly, the hepatocyte-specific antisense oligonucleotide also modulates blood plasma ceramides, suggesting that these biomarkers are regulated by ceramide biosynthesis in hepatocytes.
Review
Biochemistry & Molecular Biology
Tania C. B. Santos, Tamir Dingjan, Anthony H. Futerman
Summary: This article discusses the complexity of lipid synthesis in modern cell membranes, specifically focusing on sphingolipids (SLs). The authors introduce the concept of the 'anteome', which describes the network of metabolic pathways that must have evolved to allow for the synthesis of SLs. They also suggest that current models of life origins and evolution lack sufficient experimental evidence to explain the appearance of this complex metabolic pathway and its anteome.
Review
Biochemistry & Molecular Biology
Valeria Olguin, Anyelo Duran, Macarena Las Heras, Juan Carlos Rubilar, Francisco A. Cubillos, Patricio Olguin, Andres D. Klein
Summary: We are all similar but have some differences, which are partially due to variations in our genomes. Most animal studies are performed using a single strain, but this lack of variability can lead to inconsistent treatments when translated to humans. Sequenced organism panels are valuable tools for simulating human heterogeneity and gene mapping. This review highlights the current knowledge of mouse, fly, and yeast panels and their applications in translational research.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Multidisciplinary Sciences
Jiyoon Kim, Yael Pewzner-Jung, Tammar Joseph, Shifra Ben-Dor, Anthony H. Futerman
Summary: In this study, we generated a CerS6 mouse model using CRISPR-Cas9 technology and found that replacing the DDRSDIE motif in CerS6 may affect an unknown mechanism of regulation of ceramide synthesis in vivo, resulting in significantly reduced ceramide levels. By crossing CerS6(ADAAAIA) mice with CerS5 null mice, we demonstrated that other ceramide species with different acyl chain lengths may compensate for the depletion of C16-ceramide levels.
Review
Pharmacology & Pharmacy
Alessia Di Donfrancesco, Giulia Massaro, Ivano Di Meo, Valeria Tiranti, Emanuela Bottani, Dario Brunetti
Summary: This article provides a comprehensive overview of the application of gene therapy in mitochondrial diseases (MDs), addressing the main challenges, feasible solutions, and future prospects.
Article
Neurosciences
Shani Blumenreich, Tamar Nehushtan, Or B. Barav, Jennifer T. Saville, Tamir Dingjan, John Hardy, Maria Fuller, Anthony H. Futerman
Summary: In the past decade, several genetic risk factors, including GBA variants, have been identified for Parkinson's Disease (PD). This study analyzes lipid levels in different brain regions of PD patients with GBA mutations and suggests that changes in ganglioside levels may contribute to the association between PD and GBA mutations.
NPJ PARKINSONS DISEASE
(2022)
Article
Biochemistry & Molecular Biology
Anyelo Duran, David A. Priestman, Macarena Las Heras, Boris Rebolledo-Jaramillo, Valeria Olguin, Juan F. Calderon, Silvana Zanlungo, Jaime Gutierrez, Frances M. Platt, Andres D. Klein
Summary: Using a systems genetics approach, we identified 30 shared predicted modifier genes between hepatic lysosomal enzymes and glycosphingolipids (GSLs), clustered in three pathways and associated with other diseases. Surprisingly, these genes are regulated by ten common transcription factors and miRNA-340p. These findings suggest novel therapeutic targets for Lysosomal Storage Disorders (LSDs) and indicate the potential involvement of GSL metabolism in other pathologies.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Multidisciplinary Sciences
Iris D. D. Zelnik, Beatriz Mestre, Jonathan J. J. Weinstein, Tamir Dingjan, Stav Izrailov, Shifra Ben-Dor, Sarel J. J. Fleishman, Anthony H. H. Futerman
Summary: Researchers validate a one-step algorithm called mPROSS for stabilizing membrane proteins directly from an AlphaFold2 model structure. By applying this algorithm to ceramide synthase, they obtained a more stable form of human CerS2 enzyme through 37 designed mutations. With the help of molecular dynamics simulations, a potential pathway for substrate delivery to ceramide synthases is proposed.
NATURE COMMUNICATIONS
(2023)
Article
Cell Biology
Michael Paul Hughes, Hemanth Ramesh Nelvagal, Oliver Coombe-Tennant, Dave Smith, Claire Smith, Giulia Massaro, Laura Poupon-Bejuit, Frances Mary Platt, Ahad Abdul Rahim
Summary: This article introduces a novel small truncated endogenous NPC1 promoter that has high gene expression both in vitro and in vivo. The researchers demonstrate that this promoter provides optimal therapeutic efficacy in mouse models of NP-C, including increased survival, improved behavioral phenotypes, and attenuated neuropathology. Therefore, they propose that this novel promoter can greatly enhance the efficiency of designing an optimized AAV9 vector for gene therapy for NP-C.
Article
Multidisciplinary Sciences
Andres D. Klein, Tiago Fleming Outeiro
Summary: GCase mutations lead to glucosylceramide build-up in the lysosome, affecting alpha-synuclein aggregation and autophagy. Recent findings also reveal the presence of GCase in mitochondria, where it supports mitochondrial complex I function and energy metabolism. This new understanding of GCase's role in mitochondria could lead to novel therapeutics for Parkinson's and Gaucher's disease.
NATURE COMMUNICATIONS
(2023)
Article
Clinical Neurology
Roy Avraham, Sharon Melamed, Hagit Achdout, Noam Erez, Ofir Israeli, Moria Barlev-Gross, Metsada Pasmanik-Chor, Nir Paran, Tomer Israely, Einat B. Vitner
Summary: Virus-induced CNS diseases impose a significant burden on human health globally, and the lack of effective antiviral drugs and vaccines is a major challenge. This study suggests that altering glycosphingolipid levels through UGCG inhibitors could be a potential therapeutic strategy. Inhibiting UGCG reduced viral replication and increased survival rates in mice infected with neuroinvasive Sindbis virus, highlighting the importance of glycosphingolipids in the host immune response.
BRAIN COMMUNICATIONS
(2023)
Article
Chemistry, Multidisciplinary
Zoe Whiteley, Giulia Massaro, Georgios Gkogkos, Asterios Gavriilidis, Simon N. Waddington, Ahad A. Rahim, Duncan Q. M. Craig
Summary: Nanogels produced by microfluidics are a new alternative for the production of AAV vectors with comparable yields to traditional transfection reagents. The optimized nanogels showed no significant difference in titer compared to traditional reagents, but at lower costs.
Article
Biochemistry & Molecular Biology
Shani Blumenreich, Doreen Padan Ben-Yashar, Tali Shalit, Meital Kupervaser, Ivan Milenkovic, Tammar Joseph, Anthony H. Futerman
Summary: Gaucher's disease is caused by a defective enzyme called acid beta-glucosidase. This study used a mouse model of neurological Gaucher's disease to identify differentially expressed proteins in the brain. The researchers discovered that a protein called transglutaminase 1 was highly expressed in the brains of the diseased mice. These findings provide further insights into the pathological mechanisms of neurological Gaucher's disease.
JOURNAL OF NEUROCHEMISTRY
(2023)