Massachusetts General Hospital (MGH) investigators have discovered the mechanism by which cells sense dysfunction of the proteasome – a cellular component that degrades unneeded or defective proteins – and respond in a previously undescribed manner, by editing the amino acid sequence of a key sensing protein. Proteasome dysfunction can lead to the type of buildup of aberrant proteins that characterizes neurodegenerative disorders such as Alzheimer’s disease and is also seen in normal aging. The report is being published in the journal Cell.
The proteasome is comprised of around 20 proteins that form a structure in which unneeded cellular proteins are disposed of in a highly regulated manner. Healthy cells respond to protease dysfunction by increasing production of its component proteins. Two years ago investigators Gary Ruvkun, PhD senior author of the Cell paper, and lead author Nicolas Lehrbach, PhD – both of the MGH Department of Molecular Biology – identified a cascade of sensing and signaling proteins, including the transcription factor SKN-1A, that allows cells in the C. elegans roundworm to detect and respond to proteasome dysfunction.
The Cell paper, co-authored by Peter Breen of Ruvkun’s lab, describes how SKN-1A and its mammalian counterpart Nrf1 are modified by the
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