Using time-lapse imaging to follow the path of mutant huntingtin protein from expression through cell death, researchers believe they have laid to rest a much-debated theory of pathogenesis of Huntington's disease. Writing in the PNAS Early Edition, Cynthia McMurray, Eugenia Trushina, and their colleagues at the Mayo Clinic in Rochester, Minnesota, provide evidence suggesting it is the full-length mutant huntingtin (mhtt) that is primarily responsible for cell death, not a protein fragment that has demonstrated toxicity in vitro.

A leading theory has held that proteolysis of mhtt generating a toxic N-terminal peptide is a critical factor in neurodegeneration in Huntington's disease, and there is, indeed, much in vitro evidence that these peptides can enter the nucleus to disrupt gene transcription. However, the same group recently reported that proteolysis of mhtt in vivo may be slow in human HD tissue, and evidence from several laboratories suggests that the full mhtt protein may exert the initial and/or primary damage out in the cytoplasm, followed only later by transcriptional disruption.

In this experiment, the researchers followed the trail of mhtt in cultured primary neurons and myocytes, from the point of transfection with full-length mhtt plasmids, until cell death. Single-cell, time-lapse microscopy allowed them to measure the subcellular location of the protein and establish the sequence of toxicity. The primary toxic events occur in the cytoplasm, they write, involving the destabilization of microtubules. It is only following this disruption of the cytoskeleton that mhtt enters the nucleus. Transcriptional interference at this point could be the fault of either the full protein or the N-terminal fragment.

"Cytoplasmic dysfunction is primary because stabilization of microtubules with taxol inhibits cell death, despite the potential for generating small N-terminal fragments and consequent transcriptional dysfunction," argue the authors.

The progress of the disease in humans also argues against a primary role for the N-terminal fragment, they add. Since the mutant protein is present from early development, it would be necessary to explain why the toxic fragments would only cause the disease in later life. A simpler explanation, they suggest, is that the gradual disruption of microtubules underlies the late appearance and progression of the disease. This study appears to agree with two papers published last week on axonal transport in Huntington’s (see ARF related news story). In fact, Trushina and colleagues note unpublished data on deficits in vesicular trafficking in the presence of mutant huntingtin.—Hakon Heimer


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News Citations

  1. Huntington’s Protein Snarls Axonal Traffic

Further Reading

Primary Papers

  1. . Microtubule destabilization and nuclear entry are sequential steps leading to toxicity in Huntington's disease. Proc Natl Acad Sci U S A. 2003 Oct 14;100(21):12171-6. PubMed.