BMI SEMINAR // Vittorio Maglione - Sphingolipid metabolism: new perspectives for treating Huntington's disease

Huntington's disease (HD), the most common dominantly inherited neurodegenerative disorder is characterized by a progressive striatal and cortical neurodegeneration associated with cognitive and behavioral disturbance.
So far, many are the aberrant molecular mechanisms described to be associated with the disease, however much remains to be defined. In the last decade, perturbed metabolism of gangliosides, glycosphingolipids most abundant in the brain, has been described to play an essential role in the pathogenesis of the disease. In this context, we have contributed to demonstrate that metabolism of GM1 ganglioside is impaired in HD and its modulation results therapeutically effective in different HD pre-clinical models.
More recently, our research has revealed that sphingolipid breakdown is not restricted to ganglioside metabolism, but it also affects regulation of Sphingosine-1-phosphate (S1P), a potent signaling lipid that regulates a number of processes essential to cellular homeostasis, and viability. S1P metabolism is significantly disrupted in HD, even at early stage of the disease and, importantly, modulation of its metabolism/axis results beneficial in multiple HD pre-clinical models.
To date, there exists a variety of molecules/drugs that selectively target S1P metabolism/axis, currently used in clinical trials for human disorders. Progress in the understanding of S1P biology in HD would definitely enhance therapeutic perspectives for the treatment of the disease, by taking advantage from the already available molecules and by promoting the development of new ones.