NEW YORK (Reuters Health) - Protein aggregates that underlie nearly all neurodegenerative disorders are toxic before they form intracellular inclusion bodies, new research findings show.
In fact, these aggregates seem to be even more destructive before they are sequestered within inclusion bodies, which are diagnostic of diseases such as Alzheimer’s disease and Huntington’s disease, senior investigator Dr. Ron R. Kopito told Reuters Health.
“One of the big unsolved mysteries in understanding these diseases is understanding the relationship between protein aggregation, which seems to be a nearly universal feature of these types of diseases, and the actual cellular and molecular events that initiate and execute the process of cell death, which is the thing that in most cases causes the disease itself,” Dr. Kopito said in an interview.
Another characteristic feature of these disorders is impairment of the ubiquitin-proteasome system (UPS), which is responsible for ridding cells of misfolded and damaged proteins. One theory has suggested that loss of UPS function is due to degradation-resistant aggregated proteins “choking” the proteasome subunit.
But as Dr. Kopito’s group reports in the February 4th issue of Molecular Cell, even though proteasome components are found within inclusion bodies, proteasomes do not appear to be tightly bound to aggregated proteins. Moreover, protein aggregates do not inhibit proteasome-mediated degradation of substrates in vitro.
The researchers now theorize that inclusion bodies may actually be cytoprotective.
“Several studies have suggested that the ability to form inclusion bodies is linked to improved survival for the cell, and our paper strongly supports that hypothesis,” Dr. Kopito said.
Potential new drugs targeting protein aggregation should be directed to early events in this process while protecting inclusion body formation, the authors conclude.
Source: Molecular Cell 2005;17:351-365. [ Google search on this article ]
MeSH Headings:Inclusion Bodies: Multienzyme Complexes: Neurofibrils: Neurofibrillary TanglesCopyright © 2002 Reuters Limited. All rights reserved. Republication or redistribution of Reuters content, including by framing or similar means, is expressly prohibited without the prior written consent of Reuters. Reuters shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. Reuters and the Reuters sphere logo are registered trademarks and trademarks of the Reuters group of companies around the world.
