Inclusion bodies acquitted

Inclusion bodies play a protective, not pathogenic, role in Huntington disease, according to this week's Nature cover study by Steven Finkbeiner, from the Gladstone Institute of Neurological Disease. The paper contributes to an ongoing debate about the role of inclusion bodies—intracellular clumps of mutant huntingtin (Htt) protein—in the pathology of diseases like Huntington's and spinocerebellar ataxia.Finkbeiner and colleagues at the University of California, San Francisco, used a robotic microscope to track the decline of cultured cells infected with mutant Htt—a line of primary neurons developed in 1998 by Finkbeiner to model Huntington disease. Because the researchers could return to the same cell repeatedly, they were able to track disease progression and closely monitor the factors contributing to a cell's fate. "It's really the ability to follow a single neuron over its entire lifetime… that helped us piece together the story," Finkbeiner told The Scientist. His group found that cells with multiple inclusion bodies were more likely to survive than those without any. "These clumps, when they form, actually predict better survival, not worse, which is just the opposite of what people had been thinking."While some scientists have argued that inclusion bodies cause neuronal death, others hold that they are a generic coping mechanism, allowing cells to sequester all the toxic proteins in one place. Still others claim that the formation of inclusion bodies is purely coincidental and unrelated to disease progression.Finkbeiner and his colleagues wrote in their paper that regardless of the subcellular location of inclusion bodies—whether they formed in the nucleus or the cytoplasm—their presence still increased the chance of cell survival. He told The Scientist that the nucleus is an important site in disease progression, but only for diffuse proteins. He also pointed out that inclusion bodies themselves "are not good in some absolute sense," but are less harmful than the alternative, which is diffuse cytotoxic proteins.Christopher Ross, director of the neurobiology division in Johns Hopkins University's psychiatry department and long-time polyglutamine disease investigator, told The Scientist that the results are "quite consistent with an emerging idea in the field, that inclusions are an active cellular response to abnormal proteins."Ross said that one important concept omitted from Finkbeiner's paper is that of the aggresome, a central location in the cell where aberrant proteins that can't be degraded by normal processes are sent for recycling—an idea first proposed by Stanford neurobiologist Ron Kopito in 1998 and consistent with the notion that inclusion bodies are beneficial. "The idea is that that's a cellular protective mechanism," Ross explained. "However, there has been no direct evidence for that idea and certainly nothing as dynamic or elegant as this demonstration in cell culture… What Finkbeiner has done is really proved that the ideas behind that concept are valid."In his accompanying News and Views article, University of Minnesota geneticist Harry T. Orr said, "It will… be interesting to see whether the results end the debate on the pathogenic role of inclusion bodies in polyglutamine diseases. If they don't, one wonders what would."Ross agreed: "This has been an uncertain and controversial area. There has been an emerging idea that inclusions are protective, and this paper really elegantly and conclusively shows that." He said, "It's not surprising, but it's very important not just for Huntington's, but for Alzheimer's and Parkinson's and other neurodegenerative diseases, because I think the aggresome concept is going to be relevant for all of them." "The burning question now in the field is, what is the molecular species that's toxic?" added Ross. He speculated that small oligomers will eventually be identified as the culprit, but for now, "what this paper will do is lay to rest the inclusion issue and let people focus on the issue of monomers versus oligomers."

Inclusion bodies acquitted

In Huntington's disease, clumps of mutant protein seem to be protective rather than harmful

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