Mechanism Underlying Premature Aging in Cockayne Syndrome Revealed; Mitochondrial Defects Reversed by Inhibitors of HTRA3 Protease in Vitro

Rare genetic diseases cause accelerated premature aging. To date, there is no treatment for these pathologies. Understanding the causes of premature aging diseases may also help elucidating the process of normal aging. One such disease, Cockayne syndrome (CS), has an incidence of approximately 2.5 per million births and, in its most severe form, is associated with a life span of under seven years. Children with Cockayne syndrome show marked signs of premature aging, such as loss of weight, hair, hearing, and sight, as well as facial deformation and neurodegeneration. Cockayne syndrome is caused by mutations in either of two genes involved in the repair of DNA damage induced by ultraviolet (UV) rays. CS patients are hypersensitive to sunlight and burn easily. For decades it was believed that the premature aging process associated with this disease was essentially caused by DNA repair deficiency. By comparing cells from CS patients and from patients with another, related syndrome causing only UV hypersensitivity, a research team led by Dr. Miria Ricchetti (Institut Pasteur) with Dr. Laurent Chatre (CNRS, at the Institut Pasteur), in collaboration with Dr. Alain Sarasin (CNRS, at the Institut Gustave Roussy) and Dr. Denis Biard (CEA), discovered that the defects in CS cells are actually due to excessive production of a protease (HTRA3), and induced by oxidative cell stress. The results were published online on May 18, 2015 in PNAS. The article is titled “Reversal of Mitochondrial Defects with CSB-Dependent Serine Protease Inhibitors in Patient Cells of the Progeroid Cockayne Syndrome.” In CS cells, HTRA3 degrades a key component of the machinery responsible for DNA replication in mitochondria (the cellular "powerhouses"), thereby affecting mitochondrial activity.
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