MOLECULAR PATHOGENESIS OF MITOCHONDRIAL NEURO-GASTRO-INTESTINAL ENCEPHALOMYOPATHY (MNGIE)

MNGIE (Mitochondrial Neuro GastroIntestinal Encephalomyopathy) is a rare, but devastating, hereditary (autosomal recessive) disease characterized by severe neuromuscular and gastrointestinal symptoms that tipically develop during teenage years and slowly progress for decades. Most patients die in early adulthood. In 1999, the gene responsible for this disease has been identified. It encodes an enzyme called thymidine phosphorylase. The mutations in this gene cause the loss of the enzyme activity and a consequent elevation of thymidine and uridine in plasma. Most probably, this is responsible for the accumulation of secondary genetic errors in the mitochondrial DNA, a small DNA molecule crucial for energy requirements of the cells. In fact, thymidine is one of the letters needed for DNA synthesis, and its unbalance may be toxic. To date, we dont know how increased thymidine levels may exert a toxic effect possibly inducing the mitochondrial DNA alterations in these patients. The proposed project is aimed to assess the consequences of the MNGIE mutant gene in three ways:1) performing studies on multiple autopsy tissues from MNGIE patients and from animal models of the disease to characterize the histological, biochemical and genetic alterations.2) growing normal skin cell lines exposed to high concentrations of thymidine and uridine in order to exert their toxic effect on mitochondrial DNA.3) measuring the levels of thymidine and uridine in the different autopsy tissues from MNGIE patients and from animal models to see if their imbalance leads to mitochondrial DNA defects.These studies may suggest possible therapies which, at this time, are only symptomatic. If these experiments demonstrate that thymidine and uridine elevetion is toxic, pharmacological agents that remove circulating thymidine and uridine could be tested. Furthermore, therapies using cells with normal enzimatic activity, such as bone marrow transplantation, could be experimented.