How huntingtin kills neurons?

Researchers have revealed new clues to how a defective form of the huntingtin protein may cause the deadly changes that lead to Huntington's disease -- by potentially disrupting the process of neurogenesis, thereby decreasing neural progenitor cells.

Huntingtin protein
Image: Wikimedia commons,
Jawahar Swaminathan and MSD
staff at the European Bioinformatics Institute

"[This is] the first study to demonstrate that normal huntingtin has fundamental developmental roles in mitotic spindle function during development and in the process of neurogenesis," said linkurl:Mark Mehler,;http://neuroscience.aecom.yu.edu/faculty/secondary_faculty_pages/mehler.html a neurologist at the Albert Einstein College of Medicine who was not involved in the study. Mehler previously found that in Huntington's, and other neurodegenerative diseases, this kind of defect can lead to neuronal death later in life. In Huntington's disease, mutations in the huntingtin protein lead to progressively severe psychiatric, cognitive, and motor dysfunction through the death of brain cells. The research, published in Neuron on August 12 by linkurl:Sandrine Humbert;http://www.curie.fr/fondation/index.cfm/lang/_gb.htm and her team at the Institut Curie in Orsay, France, is the first to uncover the huntingtin protein's role in neuronal development, a process that may be related to the disease's deadly effects. Huntingtin has previously been implicated in a variety of cellular functions, including signaling, transport, binding and apoptosis. The protein is expressed in many tissues, and is required for normal development in mice, but is especially highly expressed in the brain. "When you ask a researcher about [the function of the huntingtin protein and gene], people cannot give you a single answer, because the range of functions and protein partners they interact with is extraordinarily broad," said Mehler. However, researchers had not yet looked at huntingtin's role in mitosis, even though there has been clues. The protein is known to interact with microtubules and the dynein/dynactin complex, which helps form the mitotic spindle and provides the pulling force which divides the chromosomes. Huntingtin is also heavily expressed and localized to centrosomal regions in dividing cells. "For a while it has been known that huntingtin was involved in vesicle transport; they took it a step further to ask what else might be impacted by it," said linkurl:Scott Zeitlin,;http://www.medicine.virginia.edu/basic-science/departments/neurosci/faculty/zeitlin/?searchterm=%20Scott%20Zeitlin a neuroscientist at the University of Virginia School of Medicine who was not involved in the study. The process of neurogenesis -- during which neuronal precursor cells divide and give rise to neurons -- depends on correct cell division and spindle formation. When Humbert and her team silenced huntingtin in dividing cells, the cells were unable to correctly orient their spindles. As a result, dividing progenitor cells become misaligned, and consequently produce more neurons, instead of more neuronal progenitor cells. Without these neuronal progenitor cells, the brain can't make more neurons later in life as older neurons die. "Some people have, for a while, hypothesized that there could be a developmental aspect for Huntington's disease, this at least gives you a window of where to look to see where it may be occurring," said Zeitlin. "Most people think of this disease as a late-onset disorder, but there are always things that could be laid down early in development that could predispose these neurons to problems later." However, it's not yet clear that these effects of the huntingtin protein ultimately are behind the pathology of Huntington's disease. "[It will be] interesting in the future to see if the huntingtin disease mutation will impact this normal function," said Zeitlin. Humbert did not respond to requests for comment. Godin et al., "Huntingtin is required for mitotic spindle orientation and mammalian neurogenesis," Neuron 67, 392-406, 2010. Correction (August 17): When originally posted, the article said a quote from Mehler was referring to the current study, when it was instead referring to his own work. The Scientist regrets the error, and the quote has been replaced with another that refers to the current study.
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[15th February 2007]