The proteasome, that large subcellular grinder that recycles protein, plays a major role in localized degeneration of axons, according to a report in this week's Neuron. Such neuronal damage typically follows traumatic injury, but it can also be caused by a variety of neurodegenerative diseases, including Alzheimer's.
Principal author Zhigang He and colleagues at the Children's Hospital and Harvard Medical School, Boston, and Stanford University, California, examined the role of the proteasome in Wallerian degeneration, the delayed though rapid deterioration of axons on the distal side of a lesion.
Joint first authors Qiwei Zhai and Jing Wang asked what effect inhibitors of the proteasome machinery may have on the Wallerian process. They found that both reversible (the peptide MG132) and irreversible (lactacystin) proteasome inhibitors, while having no effect on normal cultured neurons, significantly delayed degeneration of axons after they were severed. In the absence of the inhibitors, fragmentation of the axon skeleton was clearly visible within eight hours, but in their presence, this process was delayed by at least another eight hours. Furthermore, the authors found that MG132 could slow down depolymerization of tubulins, suggesting that the proteasome is involved in the degeneration of microtubules.
The proteasome, being the final destination for proteins tagged for proteolytic degradation, is intimately associated with the ubiquitination pathway, one which flags proteins with strings of the small peptide ubiquitin. To test the relationship between Wallerian degeneration and the ubiquitin proteasome system, Zhai and Wang engineered neurons to express a yeast ubiquitin protease that can effectively reverse protein ubiquitination. The authors found that in these cells, about 40 percent of axons had degenerated eight hours after being severed, whereas in control cells, that percentage was typically about 90.
The results tie in with earlier observations that axons of Wlds mice, which exhibit slow Wallerian degeneration, are somehow protected by a mutation that leads to expression of a chimeric protein containing a ubiquitin conjugation factor (see ARF related news story). In the present study, however, Zhai, Wang, and colleagues extend the observations beyond Wallerian degeneration by showing that MG132 also prevents degeneration in whole axons deprived of nerve growth factor, implying that the proteasome may be involved in other types of neurodegeneration.—Tom Fagan
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- Zhai Q, Wang J, Kim A, Liu Q, Watts R, Hoopfer E, Mitchison T, Luo L, He Z. Involvement of the ubiquitin-proteasome system in the early stages of wallerian degeneration. Neuron. 2003 Jul 17;39(2):217-25. PubMed.