Title : New perspectives for a more suitable therapeutic approach for 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. The disease-causing mutation is an polyglutamine (polyQ) stretch (>36 repeats) in N-terminal region of huntingtin, a ubiquitous protein with multiple functions.
So far, many are the aberrant molecular mechanisms described to be associated with the disease, however much remains to be defined. In the past years, we have described that sphingolipid (ganglioside) metabolism is also perturbed in HD. In particular, we have found a significant reduction of ganglioside GM1 levels both HD preclinical models and HD patient.
New data indicate that lipid breakdown is not only restricted to ganglioside metabolism, but it also affects regulation of Sphingosine-1-phosphate (S1P), a potent signaling sphingolipid that regulates a number of processes essential to cellular homeostasis, and viability. Our findings indicate that S1P metabolism is significantly disrupted in HD even at early stage of the disease and importantly, revealed that such a dysfunction represents a common denominator among multiple disease models ranging from cells to humans through mouse models. Interestingly, the in vitro anti-apoptotic and the pro-survival actions seen after modulation of S1P-metabolizing enzymes allows this axis to emerge as a new “druggable” target and unfolds its promising therapeutic potential for the development of more effective and targeted interventions against this incurable condition.