A Common Pathway for a Rare Disease?

Science  20 Dec 2013:
Vol. 342, Issue 6165, pp. 1453-1454
DOI: 10.1126/science.1248449

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Leigh syndrome is a fatal, infantile neurodegenerative disease first described more than 60 years ago (1). Children with Leigh syndrome typically are born with normal prenatal development, but decline after intermittent episodes of encephalopathy and metabolic acidosis, leading to death within the first few years of life. The diagnosis is based on magnetic resonance imaging of the brain, which reveals bilaterally symmetric lesions in the brainstem and basal ganglia (see the figure) that correspond to regions of necrosis, gliosis, and hypervascularity, with relative sparing of neurons in the early stages of the disease. At present, no effective therapies are available for Leigh syndrome, and the mainstay of management is supportive care. On page 1524 of this issue, Johnson et al. (2) demonstrate that rapamycin, a compound that inhibits a protein kinase called mechanistic target of rapamycin (mTOR), delays the onset and progression of neurological symptoms in a mouse model of Leigh syndrome. mTOR lies at the hub of cellular signaling, sensing nutrient availability to regulate protein translation, autophagy, and metabolism. The new connection to mitochondrial disease widens our view of the signaling pathway, with potential therapeutic implications.