PerspectiveMolecular Biology

Ribosome rescue and neurodegeneration

Science  25 Jul 2014:
Vol. 345, Issue 6195, pp. 378-379
DOI: 10.1126/science.1257193

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Summary

Many human cognitive and neurodegenerative diseases are caused by alterations in the amounts of specific neuronal proteins, which are maintained at proper levels by regulation of their synthesis and turnover. For example, fragile X syndrome, a neurologic disease characterized by intellectual impairment and many behavioral symptoms including autism (1), results from loss of fragile X mental retardation protein (FMRP). FMRP normally reduces the synthesis of synaptic and other proteins (2). It achieves this by stalling ribosomes that are translating messenger RNA (mRNA) into protein. Aberrant protein synthesis that arises from the absence of FMRP is linked to neuron dysfunction. On page ARTICLE455 of this issue, Ishimura et al. (3) reveal that loss of a protein that functions to release similar stalled ribosomes is linked to neuronal degeneration, but surprisingly, only in the presence of a second mutation in the protein synthesis machinery. This finding informs both critical translation mechanisms in the brain and the impact of modifying genes on disease symptoms. It thereby establishes a paradigm for understanding how a person's genetic makeup affects whether a specific mutation will lead to disease or be tolerated.