Dissecting the pathogenetic mechanisms caused by alteration of lipid homeostasis in NLSDM

There are over 8,000 known rare diseases but today treatment exists for only around 300 of these. They are mostly genetic diseases that affect patients of any age, sex or ethnic origin and involve any type of medical specialization. Over 30 million people are affected in Europe alone. In this contest, we propose a project aimed to dissect the pathogenetic mechanisms involved in Neutral Lipid Storage Disease with Myopathy (NLSDM), a rare disorder characterized by severe accumulation of neutral lipids, including triglycerides (TGs) and cholesterol esters (CEs), that misses specific pharmacological or metabolic treatments. People affected by NLSDM accumulate large amounts of triglycerides, particularly in skeletal and cardiac muscles. All patients are reported to suffer from muscle weakness and myopathy. Cardiomyopathy is present in almost 40% of reported cases. Mild hepatosteatosis is described in 25% of subjects. One third of the patients develops diabetes, suggesting a possible link between carbohydrate and lipid metabolism. Neutral lipids accumulate inside the cells in lipid droplets (LDs), highly dynamic organelles involved in cells signaling, vesicles trafficking, and fuel source for mitochondria. Many proteins, necessary to LDs functions, bind the LDs surface and some of them have an important role in lipolysis and lipophagy, as activators or inhibitors of these processes. Impaired lipid metabolism is connected to the onset of NLSDM, as ATGL protein function is severely or totally compromised in these patients. However the molecular mechanisms occurring during pathogenesis of skeletal and cardiac tissue injury remain to be clarified. Intracellular TG lipolysis significantly contributes to fatty acid oxidation in the skeletal muscle at rest and during exercise. Even though abnormalities in fat oxidation may explain muscle fatigability in NLSDM patients, they do not give full account for the development of the decline in muscle force, the development of muscle wasting and the clinical variability that can be observed. Therefore, the identification of novel molecular players, mainly involved in the alteration of intracellular lipid homeostasis and energy supply, could be of great interest. The main objective of this project is, therefore, to deeply investigate the protein machinery (beyond ATGL) that modulates the lipolysis, lipophagy, biogenesis and degradation of LDs. The second aim is to investigate the effect of possible lipophagic, lipolytic and anaplerotic compounds that may reduce neutral lipid accumulation and support cell energy demand. The skillful combination of the proponents (Unicatt unit and UPO unit) will allow to highlight new molecular pathways involved in NLSDM, representing a step forward in our understanding of clinical, and metabolic characteristics of this disease. The attainment of the proposed aims will provide hints for pharmacological and nutritional interventions to counteract progressive myopathy or cardiomyopathy.