GLYCOSPHINGOLIPIDS IN MURINE NEURODEGENERATIVE DISEASES

Summary

Principal Investigator: THOMAS SEYFRIED
Abstract: The objective of this research is to develop an effective life long therapy for ganglioside storage diseases. The gangliosidoses are a group of incurable neurodegenerative diseases involving storage of either ganglioside GM1 or GM2 in lysosomes. GM1 gangliosidosis arises from a genetic deficiency of the acid b- galactosidase that catabolizes ganglioside GM1, whereas Sandhoff disease (SD) arises from genetic deficiency in the b-hexosaminidase b subunit that catabolizes ganglioside GM2. Ganglioside accumulation in these diseases leads to neuronal death, inflammation, and progressive neurological deterioration. Our studies will involve diverse and complimentary approaches for disease management. This research will evaluate NB-DGJ as a substrate reduction therapy, neural stem cells (NSCs), as across-correctional therapy, and caloric restriction (CR) as an anti-inflammatory therapy. NB-DGJ decreases the rate of glyco- sphingolipid (GSL) biosynthesis thereby counterbalancing an impaired rate of catabolism. NSCs provide the missing lysosomal enzyme thereby reducing GSL storage, whereas CR improves health through effects on CNS inflammatory processes. Aim 1will determine the effects of NB-DGJ on the GSL composition of postnatal brains in normal mice and in the GM1 gangliosidosis and SD mutants. This aim will determine, a) the timing and extent of brain ganglioside recovery following NB-DGJ treatment, b) the extent to which GSL synthesis inhibition delays pathological ganglioside storage in CNS tissues, and c) whether GSL synthesis inhibition delays myelin abnormalities in the storage disease mice. Aim 2 will evaluate the therapeutic potential of neural stem cell (NSC) transplantation alone and together with NB-DGJ in developing SD mice. We hypothesize that NSCs will act synergistically with and NB-DGJ to reduce accumulating GSLs and provide maximal therapeutic effect. Aim 3 will examine the influence of NB-DGJ on embryo gangliosides following in utero administration. These studies will test the feasibility of timed drug release for in utero substrate reduction therapy for GM1 gangliosidosis. Aim 4 will test the hypothesis that CR reduces CNS inflammation and that CR and NB-DGJ act synergistically in managing CNS inflammation, ganglioside accumulation, and disease progression. The proposed studies will provide essential information on combinatorial therapies for the ganglioside storage diseases and will have translational benefit to the clinic.
Funding Period: 2001-03-01 - 2010-02-28
more information: NIH RePORT

Top Publications

  1. pmc Glycolipid and ganglioside metabolism imbalances in Huntington's disease
    Paula A Desplats
    Molecular Biology Department, The Scripps Research Institute, 10550 N Torrey Pines Rd, La Jolla, CA 92037, USA
    Neurobiol Dis 27:265-77. 2007
  2. pmc Calorie restriction as an anti-invasive therapy for malignant brain cancer in the VM mouse
    Laura M Shelton
    Boston College, 140 Commonwealth Avenue, Chestnut Hill, MA 02467, U S A
    ASN Neuro 2:e00038. 2010
  3. pmc Purification, crystallization and X-ray diffraction analysis of human dynamin-related protein 1 GTPase-GED fusion protein
    Eva Klinglmayr
    Department of Molecular Biology, University of Salzburg, 5020 Salzburg, Austria
    Acta Crystallogr Sect F Struct Biol Cryst Commun 68:1217-21. 2012
  4. ncbi Restricted ketogenic diet enhances the therapeutic action of N-butyldeoxynojirimycin towards brain GM2 accumulation in adult Sandhoff disease mice
    Christine A Denny
    Department of Biology, Boston College, Chestnut Hill, Massachusetts 02467, USA
    J Neurochem 113:1525-35. 2010
  5. ncbi A novel pre-clinical in vivo mouse model for malignant brain tumor growth and invasion
    Laura M Shelton
    Boston College, Higgins Hall 140 Commonwealth Ave, Chestnut Hill, MA 02467, USA
    J Neurooncol 99:165-76. 2010
  6. ncbi Metabolic management of brain cancer
    Thomas N Seyfried
    Biology Department, Boston College, Chestnut Hill, MA 02467, USA
    Biochim Biophys Acta 1807:577-94. 2011
  7. pmc Perspectives on the mesenchymal origin of metastatic cancer
    Leanne C Huysentruyt
    Department of Medicine, Hematology and Oncology, University of California, San Francisco, San Francisco, CA, USA
    Cancer Metastasis Rev 29:695-707. 2010
  8. ncbi The EL mouse: a natural model of autism and epilepsy
    Joshua J Meidenbauer
    Biology Department, Boston College, Chestnut Hill, Massachusetts 02467, USA
    Epilepsia 52:347-57. 2011
  9. ncbi Lipid composition of whole brain and cerebellum in Hurler syndrome (MPS IH) mice
    Karie A Heinecke
    Department of Biology, Boston College, 140 Commonwealth Ave, Chestnut Hill, Boston, MA 02467, USA
    Neurochem Res 36:1669-76. 2011
  10. pmc Influence of caloric restriction on constitutive expression of NF-κB in an experimental mouse astrocytoma
    Tiernan J Mulrooney
    Tumor Biology Program, Georgetown University Medical Center, Washington, DC, United States of America
    PLoS ONE 6:e18085. 2011

Scientific Experts

  • THOMAS SEYFRIED
  • Purna Mukherjee
  • Leanne C Huysentruyt
  • Melanie A McNally
  • Laura M Shelton
  • Rena C Baek
  • Karie A Heinecke
  • Jeremy Marsh
  • John G Mantis
  • Christine A Denny
  • Frances M Platt
  • Eva Klinglmayr
  • Julian R Arthur
  • Tiernan J Mulrooney
  • Joshua J Meidenbauer
  • Ivan Urits
  • Mylvaganam Jeyakumar
  • Michael A Kiebish
  • Paula A Desplats
  • Sandra Puehringer
  • Sandra Mayr
  • Julia Wenger
  • Ella Bossy-Wetzel
  • Brandon N Peacock
  • Jakub Tolar
  • Bruce R Blazar
  • Joshua A Rosenberg
  • Katrina S Loh
  • Roderick T Bronson
  • Youngho P Kim
  • Terry D Butters
  • Evan Y Snyder
  • Robin Newlin
  • Daniel J Stuckey
  • Nicola R Sibson
  • Douglas R Martin
  • Katie Tester
  • David A Smith
  • Jean Pyo Lee
  • Gerald Fu
  • Stephen C Heinrichs
  • John P Lowe
  • Christie L Fritz
  • Nancy R Cox
  • Julie L Kasperzyk
  • Jeffrey H Chuang
  • Hua Cheng
  • Xianlin Han
  • Tim Gilmartin
  • Steven R Head
  • Elizabeth A Thomas
  • J Gregor Sutcliffe
  • Kristi E Kass

Detail Information

Publications25

  1. pmc Glycolipid and ganglioside metabolism imbalances in Huntington's disease
    Paula A Desplats
    Molecular Biology Department, The Scripps Research Institute, 10550 N Torrey Pines Rd, La Jolla, CA 92037, USA
    Neurobiol Dis 27:265-77. 2007
    ..These findings reveal novel disruptions in glycolipid/ganglioside metabolic pathways in the pathology of HD and suggest that the development of new targets to restore glycosphingolipid balance may act to ameliorate some symptoms of HD...
  2. pmc Calorie restriction as an anti-invasive therapy for malignant brain cancer in the VM mouse
    Laura M Shelton
    Boston College, 140 Commonwealth Avenue, Chestnut Hill, MA 02467, U S A
    ASN Neuro 2:e00038. 2010
    ..In addition, we show that CR can be effective in reducing malignant brain tumour growth and invasion...
  3. pmc Purification, crystallization and X-ray diffraction analysis of human dynamin-related protein 1 GTPase-GED fusion protein
    Eva Klinglmayr
    Department of Molecular Biology, University of Salzburg, 5020 Salzburg, Austria
    Acta Crystallogr Sect F Struct Biol Cryst Commun 68:1217-21. 2012
    ..Here, the expression, purification, crystallization and X-ray diffraction analysis of the Drp1 GTPase-GED fusion protein are presented, which form a basis for more detailed structural and biophysical analysis...
  4. ncbi Restricted ketogenic diet enhances the therapeutic action of N-butyldeoxynojirimycin towards brain GM2 accumulation in adult Sandhoff disease mice
    Christine A Denny
    Department of Biology, Boston College, Chestnut Hill, Massachusetts 02467, USA
    J Neurochem 113:1525-35. 2010
    ....
  5. ncbi A novel pre-clinical in vivo mouse model for malignant brain tumor growth and invasion
    Laura M Shelton
    Boston College, Higgins Hall 140 Commonwealth Ave, Chestnut Hill, MA 02467, USA
    J Neurooncol 99:165-76. 2010
    ..The VM-M3 brain tumor model therefore can be used in a pre-clinical setting for the rapid evaluation of novel anti-invasive therapies...
  6. ncbi Metabolic management of brain cancer
    Thomas N Seyfried
    Biology Department, Boston College, Chestnut Hill, MA 02467, USA
    Biochim Biophys Acta 1807:577-94. 2011
    ..Issues of implementation and use protocols are presented for the metabolic management of brain cancer...
  7. pmc Perspectives on the mesenchymal origin of metastatic cancer
    Leanne C Huysentruyt
    Department of Medicine, Hematology and Oncology, University of California, San Francisco, San Francisco, CA, USA
    Cancer Metastasis Rev 29:695-707. 2010
    ..Such cells would naturally embody the capacity to express the multiple behaviors of metastatic cells. The view of metastasis as a myeloid/macrophage disease will impact future cancer research and anti-metastatic therapies...
  8. ncbi The EL mouse: a natural model of autism and epilepsy
    Joshua J Meidenbauer
    Biology Department, Boston College, Chestnut Hill, Massachusetts 02467, USA
    Epilepsia 52:347-57. 2011
    ..Because epilepsy is a comorbid trait of autism, we evaluated the EL mouse for behaviors associated with autism...
  9. ncbi Lipid composition of whole brain and cerebellum in Hurler syndrome (MPS IH) mice
    Karie A Heinecke
    Department of Biology, Boston College, 140 Commonwealth Ave, Chestnut Hill, Boston, MA 02467, USA
    Neurochem Res 36:1669-76. 2011
    ..The accumulation of ganglioside GD3 suggests that neurodegeneration occurs in the Idua⁻/⁻) mouse brain, but not to the extent seen in human MPS IH brain...
  10. pmc Influence of caloric restriction on constitutive expression of NF-κB in an experimental mouse astrocytoma
    Tiernan J Mulrooney
    Tumor Biology Program, Georgetown University Medical Center, Washington, DC, United States of America
    PLoS ONE 6:e18085. 2011
    ..Although we have shown that CR manages tumor growth and improves survival through multiple molecular and biochemical mechanisms, little information is known about the role that CR plays in modulating inflammation in brain tumor tissue...
  11. pmc Filipin recognizes both GM1 and cholesterol in GM1 gangliosidosis mouse brain
    Julian R Arthur
    Department of Biology, Boston College, 140 Commonwealth Avenue, Chestnut Hill, MA 02467, USA
    J Lipid Res 52:1345-51. 2011
    ..The data indicate that in addition to cholesterol, filipin can also be useful for detecting GM1...
  12. pmc Glutamine targeting inhibits systemic metastasis in the VM-M3 murine tumor model
    Laura M Shelton
    Department of Biology, Boston College, Chestnut Hill, MA 02467, USA
    Int J Cancer 127:2478-85. 2010
    ..Our findings provide proof of concept that metabolic therapies targeting glutamine metabolism can manage systemic metastatic cancer...
  13. pmc Peripheral nervous system manifestations in a Sandhoff disease mouse model: nerve conduction, myelin structure, lipid analysis
    Melanie A McNally
    Biology Department, Boston College, 140 Commonwealth Avenue, Chestnut Hill, MA 02467, USA
    J Negat Results Biomed 6:8. 2007
    ....
  14. pmc Thematic review series: sphingolipids. Ganglioside GM3 suppresses the proangiogenic effects of vascular endothelial growth factor and ganglioside GD1a
    Purna Mukherjee
    Department of Biology, Boston College, Chestnut Hill, MA 02467, USA
    J Lipid Res 49:929-38. 2008
    ..The effects of NB-DNJ on HUVECs were reversed with the addition of GM3. We conclude that GM3 has antiangiogenic action and may possess therapeutic potential for reducing tumor angiogenesis...
  15. pmc Cardiolipin and electron transport chain abnormalities in mouse brain tumor mitochondria: lipidomic evidence supporting the Warburg theory of cancer
    Michael A Kiebish
    Department of Biology, Boston College, Chestnut Hill, MA, USA
    J Lipid Res 49:2545-56. 2008
    ..A mathematical model was developed to facilitate data interpretation. The implications of our findings to the Warburg cancer theory are discussed...
  16. ncbi Brain lipid analysis in mice with Rett syndrome
    Thomas N Seyfried
    Department of Biology, Boston College, Boston, MA 02467, USA
    Neurochem Res 34:1057-65. 2009
    ..1Bird) or the Mecp2 (308/y) RS mice...
  17. pmc Comparative analysis of brain lipids in mice, cats, and humans with Sandhoff disease
    Rena C Baek
    Biology Department, Boston College, Chestnut Hill, MA 02467, USA
    Lipids 44:197-205. 2009
    ..This study is the first comparative analysis of brain lipids in mice, cats, and humans with SD and will be important for designing therapies for Sandhoff disease patients...
  18. ncbi Akt-dependent proapoptotic effects of dietary restriction on late-stage management of a phosphatase and tensin homologue/tuberous sclerosis complex 2-deficient mouse astrocytoma
    Jeremy Marsh
    Biology Department, Boston College, Chestnut Hill, Massachusetts 02467, USA
    Clin Cancer Res 14:7751-62. 2008
    ..Although dietary restriction (DR) reduces glycolysis and manages early-stage astrocytoma growth, no prior studies have identified the mechanisms involved or determined if DR can also manage late-stage tumor growth...
  19. ncbi Targeting energy metabolism in brain cancer with calorically restricted ketogenic diets
    Thomas N Seyfried
    Department of Biology, Boston College, Chestnut Hill, Massachusetts 02467, USA
    Epilepsia 49:114-6. 2008
    ..The CRKD is effective in managing brain tumor growth in animal models and in patients, and appears to act through antiangiogenic, anti-inflammatory, and proapoptotic mechanisms...
  20. ncbi Improvement in motor and exploratory behavior in Rett syndrome mice with restricted ketogenic and standard diets
    John G Mantis
    Biology Department, Boston College, Chestnut Hill, MA 02467, USA
    Epilepsy Behav 15:133-41. 2009
    ..Our findings suggest that calorically restricted diets could be effective in reducing the anxiety and in improving motor behavior in girls with RTT...
  21. ncbi Influence of methotrexate and cisplatin on tumor progression and survival in the VM mouse model of systemic metastatic cancer
    Leanne C Huysentruyt
    Department of Biology, Boston College, Chestnut Hill, MA 02467, USA
    Int J Cancer 126:65-72. 2010
    ..These findings indicate that the VM-M3/Fluc tumor is a reliable preclinical model for evaluating antimetastatic cancer therapies and underlying control pathways...
  22. ncbi N-butyldeoxygalactonojirimycin reduces brain ganglioside and GM2 content in neonatal Sandhoff disease mice
    Rena C Baek
    Biology Department, Boston College, 140 Commonwealth Avenue, Chestnut Hill, MA 02467, USA
    Neurochem Int 52:1125-33. 2008
    ..Our results show that NB-DGJ is effective in reducing total brain ganglioside and GM2 content at early neonatal ages...
  23. pmc Neural stem cell transplantation benefits a monogenic neurometabolic disorder during the symptomatic phase of disease
    Mylvaganam Jeyakumar
    Department of Pharmacology, University of Oxford, Oxford, United Kingdom
    Stem Cells 27:2362-70. 2009
    ....