Comment by Ottavio Arancio and Michael Shelanski
This paper is both interesting in itself and a constant reminder of the complex roles a single protein can play in different contexts, or with various post-translational modifications. A classic example of that is the lens protein αB-crystallin that also serves as an important heat shock protein and as a chaperone for intermediate filaments.

Early work from the Lansbury laboratory showed that UCH-L1 was potentially bifunctional with both hydrolase and ligase activities depending on concentration and dimerization. The current paper adds a third function, showing the promotion of α-synuclein toxicity when UCH-L1 is membrane associated. An extremely exciting aspect of this report is the demonstration that an inhibitor of farnesylation can reduce synuclein levels and promote cell viability.

There is evidence that UCH-L1 activity is reduced in AD. Studies in our laboratory indicate that this is not due to alterations of total UCH-L1 in the brain, but to a repartitioning of the enzyme into a particulate fraction where...  Read more

Comment by Ottavio Arancio and Michael Shelanski
This paper is both interesting in itself and a constant reminder of the complex roles a single protein can play in different contexts, or with various post-translational modifications. A classic example of that is the lens protein αB-crystallin that also serves as an important heat shock protein and as a chaperone for intermediate filaments.

Early work from the Lansbury laboratory showed that UCH-L1 was potentially bifunctional with both hydrolase and ligase activities depending on concentration and dimerization. The current paper adds a third function, showing the promotion of α-synuclein toxicity when UCH-L1 is membrane associated. An extremely exciting aspect of this report is the demonstration that an inhibitor of farnesylation can reduce synuclein levels and promote cell viability.

There is evidence that UCH-L1 activity is reduced in AD. Studies in our laboratory indicate that this is not due to alterations of total UCH-L1 in the brain, but to a repartitioning of the enzyme into a particulate fraction where its enzymatic activity is very low. This results in lower levels of cytoplasmic enzyme, which normally has a much higher enzymatic activity that the particulate fraction. Thus, the total activity was decreased. If the repartitioning is due to farnesylation, then it is possible that agents such as FTI-277 that was used in these studies might be of value in treatment of AD by raising the levels of active, cytoplasmic UCH-L1. We eagerly await the results of studies using this agent in models of AD.

View all comments by Michael Shelanski