Discovery of a new protein triaging pathway for neurotoxic proteins

2016

Challenge

In multicellular organisms, the cell-to-cell transmission of misfolded proteins can propagate abnormal polypeptides throughout a tissue, such as the brain. This process is accelerated when transmitted polypeptides act as a template for further protein misfolding in recipient cells. The accumulation of these misfolded proteins can lead to widespread cell death, which is characteristic of many neurodegenerative diseases. Although the link between protein misfolding and several diseases is well known, it is currently unclear how misfolded proteins can be released from donor cells to initiate further misfolding in recipient cells.

Advance

IRP researchers led by Yihong Ye, Ph.D., discovered a novel protein triaging pathway that is dedicated to the removal of misfolded cytosolic proteins. The pathway uses an endoplasmic reticulum-associated enzyme to recruit misfolded cytosolic proteins and package them into vesicles marked for cellular secretion.

Impact

Having identified this unconventional protein secretion pathway for misfolded proteins, Dr. Ye’s group is now assessing whether or not this process may contribute to the cell-to-cell propagation of misfolded proteins, which is the underlying cause of the neurodegeneration seen in Alzheimer’s, Parkinson’s, and Huntington’s diseases. If this pathway is shown to play a role in the propagation of misfolded proteins, it could offer a promising target for strategies to combat these serious neurological diseases. 

Publications

Lee JG, Takahama S, Zhang G, Tomarev S, Ye Y. (2016). Unconventional secretion of misfolded proteins promotes adaptation to proteasome dysfunction in mammalian cells. Nat. Cell Biol. 18(7):765-76.