New research coming out of the University of Rochester suggests that inducing neurogenesis could be a possible treatment option for Huntington’s Disease.

Huntington’s Disease (HD) is a rare, autosomal dominant disease. The effects of HD are generally both physical and mental. Those afflicted with HD generally have erratic movements, slurring of speech, unsteady walking and uncoordinated facial expressions. As the disease progresses, patients typically lose the ability to feed themselves and require full-time care. Cognitively, patients lose their spatial skills, abstract thinking, planning and ability to learn new skills.

HD, unfortunately, has an extremely late onset which typically means the affected individual already has a family. Since HD is a dominant gene, only one parent must have the mutation to pass it on to their kids. The disease is caused by a number of repeats in the Interesting Transcript 15 gene, which encodes the huntington protein. Those with HD exhibit neurodegeneration throughout the brain, the neostratium in particular. The exact role of this protein in neurodegeneration, however, is still unknown.

Research headed by Sung-Rae Cho at the University of Rochester shows that inducing neurogenesis in striatal neurons slows the onset of HD, increasing life expectancy and reducing cognitive impairments in mice.

Details about the study after the jump

Neural Stem Cells

Neural stem cells are cells that have the capability to either divide and retain their stem-cellness (a technical term, I swear) or terminally differentiate into neurons. They can be found in the ventricular subependymal region, as well as a few other places. If you dump brain-derived neurotrophic factor (BDNF) into this region, neurogenesis and migration increases dramatically. The neostratium receives some of these newly minted cells, offering a tantalizing possibility of HD treatment by coaxing newly created neurons into the region.

Unfortunately, most of the neurons that differentiate and migrate from the subependymal region either die or differentiate into glial cells. Previous work has shown that this preference for glial differentiation can be caused by bone morphogenetic proteins (BMPs). The research team overexpressed Noggin, which is an inhibitor of BMPs, in hopes of knocking down the differentiation of glial cells. Overexpression of both BDNF and Noggin was shown to substantially increase neuronal differentiation. Furthermore, most of these cells differentiated into medium spiny neurons, a type of neuron predominantly lost during the course of HD.

Interestingly, in mice that overexpressed BDNF/Nogging, neurons that migrated to the striatal region included both types of medium spiny neurons (enkephalin and substance-p expressing). This is particularly interesting because they differentiated correctly despite the HD disease environment. The two different types of neurons each project into different regions of the brain and both are lost during the course of HD.

Not just neurogenesis is needed

Of course, just growing new neurons is not sufficient to restore damage done by the disease. To do that, the new neurons must extend processes (axons, dendrites) to the correct regions. To test this this, the lab injected tiny amount of retrograde tracer into the regions that the new neurons should be connecting to. It was found that the new neurons, after a period of time, had taken up the tracer from the regions.

Furthermore, enkephalin and substance-p neurons send their processes to different regions. It was shown that both types extended processes to the correct region, again despite the HD disease environment. The newly differentiated neurons were migrating to the striatal region and sending processes to their normal targets, a good sign that this process could restore function lost to HD.

And it seems to have helped. Mice that overexpressed BDNF/Noggin showed significant slowing of motor control loss when compared to controls. Testing of motor control, however, became unreliable after 13 weeks because too many of the control mice had died relative to the BDNF/Noggin mice, skewing results to an unacceptable degree. Indeed, BDNF/Noggin mice lived on average 16% longer than controls, also a very good indicator of the BDNF/Noggin effectiveness.

Lastly, the lab wanted to make sure the increased survival rates and decreased motor loss was not the result of BDNF, which has been shown to be neuroprotective in nature. They injected Ara-C, an inhibitor of mitosis. Ara-C is highly effective at stopping neurogenesis by suspending mitosis, preventing new neurons from being created. It was found that the application of Ara-C to overexpressing BDNF/Nogginc mice completely removed all benefits gained from the overexpression. This strongly suggests that the increased performance was due to neurogenesis and not the neuroprotective properties of BDNF.

Possible treatment option?

An interesting note is how the overexpression was accomplished. Overexpression of BDNF/Noggin was done with adenoviral gene expression, which is transient. This transient expression lasts no more than 2 months, yet the overexpressed mice gained significant benefit many months after. It is theorized that sustained expression of BDNF and Noggin could provide a strong treatment option for HD.

The method of neurodegeneration due to HD is still relatively unknown, precluding a complete cure. This research, however, offers hope that extended treatment can be offered to HD patients.

References

Cho S, Benraiss A, Chmielnicki E, Samdani A, Economides A, Goldman S. Induction of neostriatal neurogenesis slows disease progression in a transgenic murine model of Huntington disease. J Clin Invest. 2007, [E-Publication, ahead of print]. DOI: 10.1172/JCI31778