Molecular Zipcodes Provide Address for HD Protein

HD Lighthouse Contributing Editor's Comment: The last few months have seen some exciting developments in basic HD research with implications for drug development and therapy. A new study by Dr. Ray Truant and colleagues from McMaster University have found a sequence of proteins on the HD gene which direct it into the nucleus of the cell.

Last year we covered the caspase 6 study which showed that caspase 6 resistent HD mice never developed the disease. (See HDL: Caspase 6 Resistant HD Mice Do Not Develop Huntington's Disease) Caspase 6 cleaves the HD protein into toxic fragments which enter the nucleus of the cell where they cause dysfunction in multiple ways. CHDI is funding research into the development of a caspase 6 inhibitor but does not yet have one.

This research points to a different way to address the problem, by targeting the localization signal that directs the HD protein fragments into the nucleus of the cell. According to the researchers in the studies described below, they are close to developing a small molecule which could prevent this from happening. The High Q foundation (CHDI's funding source) is funding the research.

High Q and CHDI are dedicated to finding treatments as soon as possible. This parallel approach maximizes the chance that this major pathology in HD can be addressed soon.

-- Marsha L. Miller, Ph.D.
Posted to the HDL: 14 Feb 2007

Ray Truant, associate professor, Department of Biochemistry and Biomedical Sciences.

Hamilton, Ontario (January 29, 2007) -- McMaster scientists are very close to defining small molecule drugs that should be able to redirect the huntingtin protein from accumulating in the wrong place within brain cells, which could potentially translate to a therapy for Huntington's Disease (HD).

There is currently no way to stop or reverse the progression of Huntington’s Disease, which affects one in 10,000 Americans. It is a progressive, and eventually fatal, genetic neurological disease.

Associate professor Ray Truant’s lab has discovered molecular ‘zip codes’ or protein sequences in the huntingtin protein that dictate where it goes to within a brain cell.

"We have shown that the mutant huntingtin protein is mis-localized in brain cells in Huntington’s Disease, because it is being improperly signaled, or instructed where to go in the cell," said Truant, of the Department of Biochemistry and Biomedical Sciences.

"In particular, Huntingtin is accumulating at the heart of the cell, the nucleus, where it shouldn't be. This is causing the brain cells to not function properly, and eventually die."

Truant and his university colleagues have received a $260,000 research operating grant from the American-based High Q Foundation. The grant will fund research using the technology of McMaster’s new Biophotonics Facility and the use of laser microscopy in living brain cells.

It will also use the McMaster High Throughput Screening Facility to screen for new drugs that can affect how huntingtin is signalled.

"This class of small molecule drugs we are now working with has been proven recently to be a very successful class of drugs for different diseases, but not yet in HD," said Truant.

This new type of research is called Chemical Biology and is the focus of a new graduate degree program at McMaster University. The federal Canada Foundation for Innovation recently announced a $8 million grant towards a new Centre of Microbial Chemical Biology at McMaster.

The abstract Ray Truant, Randy Singh Atwal, and Anjee Burtnik, Nucleocytoplasmic trafficking and transcription effects of huntingtin in Huntington's disease. Progress in Neurobiology 2007 Jan 19; [Epub ahead of print].

There are nine genetic neurodegenerative diseases caused by a similar genetic defect, a CAG DNA triplet-repeat expansion in the disease gene's open reading frame resulting in a polyglutamine expansion in the disease proteins. Despite the commonality of polyglutamine expansion, each of the polyglutamine diseases manifest as unique diseases, with some similarities, but important differences. These differences suggest that the context of the polyglutamine expansion is important to the mechanism of pathology of the disease proteins. Therefore, it is becoming increasingly paramount to understand the normal functions of these polyglutamine disease proteins, which include huntingtin, the polyglutamine-expanded protein in Huntington's disease (HD). Transcriptional dysregulation is seen in HD. Here we discuss the role of normal huntingtin in transcriptional regulation and misregulation in Huntington's disease in relation to potentially analogous model systems, and to other polyglutamine disease proteins. Huntingtin has functional roles in both the cytoplasm and the nucleus. One commonality of activity of polyglutamine disease proteins is at the level of protein dynamics and ability to import and export to and from the nucleus. Knowing the temporal location of huntingtin protein in response to signaling and neuronal communication could lead to valuable insights into an important trigger of HD pathology.

An abstract from an earlier published article

Jianrun Xia, Denise H. Lee, Jillian Taylor, Mark Vandelft and Ray Truant. Huntingtin contains a highly conserved nuclear export signal. Human Molecular Genetics, 2003, Vol. 12, No. 12 1393-1403.

Huntington's disease (HD), is a genetic neurodegenerative disease characterized by a DNA CAG triplet repeat expansion in the first exon of the disease gene, HD. CAG DNA expansion results in a polyglutamine tract expansion in mutant huntingtin protein. Wild-type and mutant full-length huntingtin have been detected in the nucleus, but elevated levels of mutant huntingtin and huntingtin amino-terminal proteolytic fragments are seen to accumulate in the nuclei of HD-affected neurons. The presence of huntingtin in both the nucleus and the cytoplasm suggested that huntingtin may be dynamic between these compartments. By live cell time-lapse video microscopy, we have been able to visualize polyglutamine-mediated aggregation and the transient nuclear localization of huntingtin over time in a striatal cell line. A classical nuclear localization signal could not be detected in huntingtin, but we have discovered a nuclear export signal (NES) in the carboxy-terminus of huntingtin. Leptomycin B treatment of clonal striatal cells enhanced the nuclear localization of huntingtin, and a mutant NES huntingtin displayed increased nuclear localization, indicating that huntingtin can shuttle to and from the nucleus. The huntingtin NES is strictly conserved among all huntingtin proteins from diverse species. This export signal may be important in Huntington's disease because this fragment of huntingtin is proteolytically cleaved away during HD. The huntingtin NES therefore defines a potential role for huntingtin as a member of a nucleocytoplasmic dynamic protein complex.

Source: press release

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