Important findings published online in JCB: Mediating protein aggregation in the brain

Nezis (left) and Brech.
New findings by scientists from the Department of Biochemistry - published online in a recent issue of the Journal of Cell Biology (impact factor 10,152) - reveal a protein required for formation of protein aggregates in the brain. First author is FUGE postdoc Ioannis Nezis, while senior scientist Andreas Brech is last author.
The figure shows the brain of a young fly (upper panel) and an old fly (lower panel).
Note the accumulation of Ref(2)P (green) and ubiquitin (red) in the older brain. Co-localization of Ref(2)P and ubiquitin is shown in yellow. (click to enlarge image)
The authors summarize the findings as follows:

Certain proteins have a propensity to form aggregates. Such aggregates can be harmful to cells when allowed to accumulate, as manifested in neurodegenerative diseases such as Alzheimer's, Parkinsons's and Huntington's disease, which are characterized by protein aggregation in nerve cells accopmanied by death of such cells.

Fortunately, there are mechanisms that prevent cellular accumulations of protein aggregates. One of the most important ones is called autophagy (self eating) and involves sequestration of cytosol (including protein aggregates) by double-membraned phagophores, resulting in the formation of autophagosomes. When the latter fuse with lysosomes, the seuqestered cytosolic material becomes degraded.

It has been unclear how protein aggregates are tagged for autophagic degradation, but the fact that they are ubiquitinated has provided a clue. Recently, Terje Johansen's group in Tromsø, in collaboration with Andreas Brech and Harald Stenmark at the Institute for Cancer Research, identified the ubiquitin-binding protein p62 as a factor that links protein aggregates to the autophagic machinery (click here to view article)

Now, Ioannis Nezis, a postdoc in Andreas Brech's group, has used a fruit fly model to show that p62 not only functions to tag protein aggregates for autophagy - it also actively participates in aggregate formation. Nezis showed that the fly homologue of p62, Ref(2)P, localizes to ubiquitin-positive protein aggregates, which are absent in the brains of young flies but accumulate as the flies grow older (Figure).

Importantly, flies lacking Ref(2)P failed to accumulate detectable protein aggregates, showing that Ref(2)P is required for the process of protein aggregation. Given that protein aggregates are toxic, the question arises whether p62/Ref(2)P is for the better or worse. The answer is probably that Ref(2)P is beneficial because not only detectable protein aggregates but also minute complexes of aggregating proteins are toxic. p62 probably serves as a mechanism to gather aggregating proteins into larger aggregates to facilitate their autophagic degradation.


Published online 17 March 2008:
The Journal of Cell Biology, Vol. 180, No. 6, 1065-1071
Ref(2)P, the Drosophila melanogaster homologue of mammalian p62, is required for the formation of protein aggregates in adult brain
Ioannis P. Nezis, Anne Simonsen, Antonia P. Sagona, Kim Finley, Sébastien Gaumer, Didier Contamine, Tor Erik Rusten, Harald Stenmark and Andreas Brech

Andreas Brech's group: Unit of Cellular Electron Microscopy

Department of Biochemistry