29 May 2005. Though no one is exactly sure why, loss of the ubiquitin carboxy terminal hydrolase UCHL1 appears to be linked to both Alzheimer and Parkinson disease (see ARF related news story and Choi et al., 2004). Now, a paper in this week’s PNAS online raises the intriguing possibility that UCHL1 levels might offer a yardstick for measuring neuronal lifespan. Fernando Nottebohm and colleagues at The Rockefeller University, New York, report that downregulation of UCHL1 is at least one of the things that sets replaceable, short-lived neurons apart from irreplaceable older ones.
There are, in fact, very few locations in the mammalian brain where neurons can be replaced. So far, only the dentate gyrus of the hippocampus and the olfactory bulb are known to afford such luxury. So what sets neurons there apart from those in the rest of the brain? This is what Nottebohm and colleagues set out to uncover.
First author Anthony Lombardino and colleagues used RNA profiling, laser capture microdissection, and neuronal tracers to try to ascertain expression differences in the high vocal center of male zebra finches (songbirds make great subjects for studying neural regeneration because the vocal center is rebuilt every spring). Lombardino found that UCHL1 was most consistently differentially expressed, being underexpressed in the replaceable neurons as opposed to the nonreplaceable neurons of the vocal center. The authors then examined expression of the hydrolase in mouse brain and found that there, too, the protein was underrepresented in the layers of the hippocampus and the olfactory bulb that contain replaceable neurons. In the hippocampal dentate gyrus, UCHL1 expression was over twofold lower than in the CA3 layer, while in the replaceable granule cells of the olfactory bulb, UCHL1 was over tenfold lower than in the nonreplaceable mitral cell layer.
Why levels of UCHL1 are low in these replaceable neurons is not quite clear. As the authors suggest, it might be because in those areas of the brain where neurons do get replaced, the mean age of the neurons is considerably lower than in the rest of the brain. But the authors prefer the idea that UCHL1 levels reflect life expectancy, writing that “the shared theme of impending neuronal death in spontaneous neuronal replacement and in neurodegeneration may explain the association of these two events with low UCHL1 expression levels.” But they also caution that it will be important to understand why different types of neurons have such disparate amounts of the hydrolase.
Also in this week’s PNAS, another player in the ubiquitin proteasome degradation pathway is identified as the culprit in Lafora disease, an autosomal recessive form of progressive epilepsy.
Jack Dixon and colleagues reveal that missense mutations in malin, an E3 ubiquitin ligase similar to the parkin of Parkinson disease, prevent the degradation of laforin, a phosphatase that has also been linked to the disease. Lafora disease is also characterized by the presence of inclusion bodies called Lafora bodies. Not to be confused with the proteinaceous Lewy bodies found in Parkinson disease and some forms of dementia, Lafora bodies are the result of defects in glycogen metabolism and are thought to be the cause of neurodegeneration seen in this form of epilepsy.—Tom Fagan.
Lombardino AJ, Li X-C, Hertel M, Nottebohm F. Replaceable neurons and neurodegenerative disease share depressed UCHL1 levels. Proc Natl Acad Sci U S A. 2005 May 31;102(22):8036-41. Epub 2005 May 23. Abstract
Gentry MS, Worby CA, Dixon JE. Insights into Lafora disease: Malin is an E3 ubiquitin ligase that ubiquitinates and promotes the degradation of laforin. Proc Natl Acad Sci U S A. 2005 Jun 1; [Epub ahead of print] Abstract