Aberrant autophagic vesicles in the lymphocytes from patients affected with Ataxia-Telangiectasia

INTRODUCTION: Ataxia-Telangiectasia (AT) is a rare disorder mostly characterized by cerebellar neurodegeneration and immunodeficiency. AT is caused by mutations in the Ataxia-Telangiectasia-Mutated (ATM) gene encoding a kinase, mostly localized in the nucleus and involved in cell-cycle control and DNA repair. ATM also displays a cytoplasmic localization, where its role is still poorly defined. OBJECTIVE: To evaluate potential abnormalities in the autophagic vesicle formation, which could be responsible for an inappropriate cell-clearance. METHODS: The ultrastructure of autophagic structures, such as autophagosomes (AP) and autolysosomes (AL), was analyzed by transmission electron microscopy (TEM) in lymphocytes obtained from AT patients and healthy controls and cultured at basal conditions or in a serum-starved medium. A quantitative analysis was also performed. RESULTS: In the patients at basal conditions, we found that the number of APs was 7 times higher than in the controls (14.00 vs 2.00 average number/100µm2), while the number of ALs was more than two times lower compared to the healthy subjects (2.00 vs 4.80 average number/100µm2). Under basal conditions, APs/ALs ratio was much higher in the patients than in the controls (7 vs 0.5). Under starved conditions, in the patients the number of APs did not further increase, resulting in an APs/ALs ratio comparable to the controls. CONCLUSIONS: Our data suggest an aberrant pattern of autophagic structures in lymphocytes from AT patients, characterized by an imbalance between autolysosomes and autophagosomes, suggesting an impairment in the cell clearance network.