Dottorato in MEDICINA MOLECOLARE

Titolo della tesi: HUNTINGTON DISEASE: NEW INSIGTHS INTO PATHOGENESIS AND TREATMENT

ABSTRACT Huntington disease (HD) is a mid-life-onset neurodegenerative disorder characterized by involuntary movements, personality changes and dementia. It progresses to death within 10-20 years after onset. There is currently no cure to treat this fatal disease. In HD patients, the protein huntingtin (Htt) contains an abnormal expansion of a polyglutamine tract, which leads to the selective death of striatal and cortical neurons. The functions of huntingtin, as well as the dysfunctions induced by the mutation are still poorly understood, however, the mutation confers protein toxic gain-of-function effects resulting in a broad array of molecular and cellular dysfunctions either in central or peripheral tissues. This is coherent with the evidence that the disease, long described as a disorder purely of the brain, is increasingly recognized as multi-organ systemic condition. Evidence indicates that perturbations of lipid homeostasis represent an emerging disease feature in HD. In particular, impaired (glico)sphingolipid metabolism represents the most relevant perturbation, however much remains to be clarified on its role in HD pathology and how it may affect disease pathogenesis. Over the past years, we have contributed to demonstrate the alteration of sphingolipid metabolism represents a new hallmark of the disease and a common denominator among multiple HD models. In the studies presented in this thesis, I have tested the hypothesis that modulation of such a perturbed metabolism may be proposed as novel and more targeted therapeutic strategy to manage HD symptoms. From my perspective, what makes this hypothesis potentially promising in HD, is the evidence that drugs working through sphingolipid metabolism-related pathways are already in clinical trial for different other pathological conditions.