Proteasome Inhibitor May Contribute to Development of Neurodegenerative Diseases

Cell biologists have identified a protein that may contribute to the development of neurodegenerative diseases such as Alzheimer's and Parkinson's by interfering with the cellular mechanism responsible for eliminating damaged or misfolded proteins.

Investigators at Harvard Medical School (Cambridge, MA, USA) have been studying the ubiquitin-proteasome system (UPS), the mechanism by which malfunctioning and possibly toxic proteins are removed from the cell. This system is based on the tagging of damaged proteins with ubiquitin, and the digestion of the subsequent ubiquinated proteins by the proteasome. In the current study, the investigators looked at the relation of the de-ubiquitinating heat shock protein USP14 to this mechanism.

They reported in the September 9, 2010, online edition of the journal Nature that USP14 could inhibit the degradation of ubiquitin–protein conjugates both in vitro and in cells. Treatment of cultured cells with this compound enhanced degradation of several proteasome substrates that have been implicated in neurodegenerative disease. USP14 inhibition accelerated the degradation of oxidized proteins and enhanced resistance to oxidative stress.

Since a catalytically inactive variation of USP14 had reduced inhibitory properties, the investigators believe that USP14 mediated its effects by cleavage of ubiquitin from the substrate proteins.

These findings led the investigators to conclude that, "Enhancement of proteasome activity through inhibition of USP14 may offer a strategy to reduce the levels of aberrant proteins in cells under proteotoxic stress.”

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