Final Report Summary - HDLIPIDS2011 (Role of sphingolipids in white matter dysfunction in Huntington's disease)
This research project was inspired by the lack of clear understanding of the crucial molecular mechanisms underlying the pathogenesis of Huntington’s Disease (HD) and by the need to evaluate competing therapeutic strategies for a devastating neurodegenerative disorder like this. Until now, numerous are the agents that have been identified to provide benefits, however, the number of therapeutic options remains severely limited with only symptomatic management therapies available and subsequent high costs for the Health National Systems. Thus, it becomes increasingly urgent searching for new and effective therapeutic solutions.
The experiments performed in this proposal have determined the putative role and validity of sphingolipid dysfunction in the pathogenesis of HD. Moreover, they have also suggested a potential correlation between ganglioside content and white matter integrity and function.
Collectively, all the data generated in this research project clearly indicate that ganglioside levels are altered in different models of HD and importantly also in human peripheral and brain tissues. These results confirmed previous evidence from Dr. Maglione (Maglione et al., 2010) and further corroborate the idea that sphingolipid metabolism dysfunction may contribute to the pathogenesis of the disease. In particular, the results obtained in the animal models demonstrate that ganglioside metabolism alteration may start at pre-symptomatic stage of the disease even before the obvious signs of the pathology. To our best knowledge, this is first study that characterises such dysfunction in different models of the disease and with different approaches.
In a previous study, Dr. Maglione has reported a significant beneficial effect of GM1 administration both in in vitro and in vivo HD experimental models (Maglione et al., 2010; Di Pardo, Maglione et al., 2012). Although, in the original research project Dr. Maglione proposed the use of the ganglioside as a possible future therapeutic approach in HD, during the execution of the experiments, he found out an alternative approach to reproduce the beneficial therapeutic effects of exogenous GM1 with the advantage not to be invasive. Peripheral administration of the sphingomimetic drug, FTY720, prevents motor deficit and exerts beneficial effects in a HD mouse model similar to those induced by GM1 and, importantly increases ganglioside levels in brain tissues of the same mice. These are very exciting and promising results which have the potential to be easily translated into clinical practice since FTY720 is currently in clinical trial in patients affected with Multiple Sclerosis (MS). Furthermore, considering that FTY720 is already on the market this may result in more sustainable costs for the Health National Systems.
With this research proposal Dr. Maglione has transferred specific knowledge and skills that were not previously present at IRCCS Neuromed. Dr. Maglione’s findings have further clarified the impact of sphingolipid dysfunction on HD pathogenesis providing also interesting evidences for a possible therapeutic intervention (Di Pardo et al., Hum Mol Genet 2014). The acquired scientific and technical knowledge in the field of lipid metabolism was extremely useful for the achievement of the objectives of this research proposal. Considering the notable role that lipid alterations have acquired in neurodegenerative disorders in the last ten to fifteen years, the transfer of these knowledge has greatly contributed to high competitiveness and will provide a basis for scientific advantages for IRCCS Neuromed.
The experiments performed in this proposal have determined the putative role and validity of sphingolipid dysfunction in the pathogenesis of HD. Moreover, they have also suggested a potential correlation between ganglioside content and white matter integrity and function.
Collectively, all the data generated in this research project clearly indicate that ganglioside levels are altered in different models of HD and importantly also in human peripheral and brain tissues. These results confirmed previous evidence from Dr. Maglione (Maglione et al., 2010) and further corroborate the idea that sphingolipid metabolism dysfunction may contribute to the pathogenesis of the disease. In particular, the results obtained in the animal models demonstrate that ganglioside metabolism alteration may start at pre-symptomatic stage of the disease even before the obvious signs of the pathology. To our best knowledge, this is first study that characterises such dysfunction in different models of the disease and with different approaches.
In a previous study, Dr. Maglione has reported a significant beneficial effect of GM1 administration both in in vitro and in vivo HD experimental models (Maglione et al., 2010; Di Pardo, Maglione et al., 2012). Although, in the original research project Dr. Maglione proposed the use of the ganglioside as a possible future therapeutic approach in HD, during the execution of the experiments, he found out an alternative approach to reproduce the beneficial therapeutic effects of exogenous GM1 with the advantage not to be invasive. Peripheral administration of the sphingomimetic drug, FTY720, prevents motor deficit and exerts beneficial effects in a HD mouse model similar to those induced by GM1 and, importantly increases ganglioside levels in brain tissues of the same mice. These are very exciting and promising results which have the potential to be easily translated into clinical practice since FTY720 is currently in clinical trial in patients affected with Multiple Sclerosis (MS). Furthermore, considering that FTY720 is already on the market this may result in more sustainable costs for the Health National Systems.
With this research proposal Dr. Maglione has transferred specific knowledge and skills that were not previously present at IRCCS Neuromed. Dr. Maglione’s findings have further clarified the impact of sphingolipid dysfunction on HD pathogenesis providing also interesting evidences for a possible therapeutic intervention (Di Pardo et al., Hum Mol Genet 2014). The acquired scientific and technical knowledge in the field of lipid metabolism was extremely useful for the achievement of the objectives of this research proposal. Considering the notable role that lipid alterations have acquired in neurodegenerative disorders in the last ten to fifteen years, the transfer of these knowledge has greatly contributed to high competitiveness and will provide a basis for scientific advantages for IRCCS Neuromed.