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Does failing to take out the “garbage” contribute to neurodegeneration?  New signs that aggregated proteins impair protein degradation.

CellTweet #1
July 15, 2011 

Protein aggregates—abnormal clumps of misfolded proteins—are common feature in diseases such as Parkinson’s, Huntington’s, and Creutzfeldt-Jakob (CJD, the infamous “mad cow” disease). However, it’s still a mystery as to whether these aggregates cause the disease or are simply an effect. If aggregates are the cause, how do they work?

In the May 15 issue of the journal Molecular Biology of the Cell, Ramanujan Hegde and colleagues at the National Institute of Child Health and Human Development say that protein aggregates make cells unhealthy by clogging a specific pathway of protein degradation. Normally, a subset of proteins are created and modified in a cellular compartment called the endoplasmic reticulum (ER). The ER operates like a factory assembly line. An unfolded protein is first inserted into the ER for folding into the appropriate shape. Additional protein subunits and modifications are then added to produce the final functional protein. Unfortunately, some proteins are not inserted efficiently into the ER and these proteins can’t be folded correctly. They become a form of cellular toxic waste that must be rapidly destroyed by a large protein complex called the proteasome, the cell’s garbage disposal. The degradation of these proteins is critical to the health of the cell. Yet in this study, the researchers found that these disease-associated protein aggregates interfered with this pathway of protein degradation, causing the misfolded proteins to pile up. Just imagine if no one took the garbage out at your house! This discovery identifies a new cellular process that is being sabotaged by aggregated proteins. It gives researchers a new clue into untangling the mystery of the causes of protein aggregation diseases and a possible target for drug intervention.

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MBoC Reference:

Cytosolic aggregates perturb the degradation of nontranslocated secretory and membrane proteins. Oishee Chakrabarti, Neena S. Rane, and Ramanujan S. Hegde

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