HD Lighthouse Contributing Editor's Comment: Josep Canals and colleagues have added to the growing evidence that BDNF, or brain-derived neurotrophic factor, can be highly protective of the brain. The findings of this research group, based at University of Barcelona, Spain, and Karolinska Institute, Sweden, are among recent discoveries showing that BDNF is especially consequential in Huntington’s disease (HD). The Canals et al. studies show that BDNF levels in certain brain regions influence the onset and severity of motor dysfunction in mice genetically designed to model Huntington's disease. (The Canals team studied the R6/1 mouse, one mouse model of HD).

BDNF is a major factor in the development and progress of Huntington's, because BDNF sustains the striatum of the brain, which is the brain area most affected in HD. Numerous animal studies have shown specifically that raising BDNF levels can protect the brain — particularly the striatum — in HD mouse models. The new research suggests that actively increasing BDNF levels is likely to slow the development of Huntington's symptoms, as well as protect the brain. (For further background on BDNF and other neurotrophins, a good overview is found on the HD Lighthouse through this link. For additional information, see this link to http://web.sfn.org/ and this link to http://www.ncbi.nlm.nih.gov/.)

The promising new findings about BDNF can be exploited even today — there are easy, cheap, reasonably safe ways for people to increase BDNF levels in the brain. Exercise, maintaining a reasonably low weight, and enjoying a stimulating, but not overly stressful, social and mental life all raise BDNF levels. Other BDNF enhancers include the antidepressants known as selective serotonin-reuptake inhibitors (SSRIs), such as sertraline, and a few other drugs. (One Lighthouse article on practical ways to raise BDNF levels is found via this link to http://www.hdlighthouse.org/. Some excellent information on protecting the brain through exercise and diet is found on this link to http://www.hdlighthouse.org/ and this link to http://www.hdlighthouse.org/.)

The full physiological picture behind the HD-BDNF connection is complex, but it is now at least partly understood. In people who do not have HD, the regular, non-mutated huntingtin protein, or "wild-type huntingtin" (produced by the regular huntingtin gene), is critical in stimulating BDNF production in the area of the brain called the cortex. Cortical neurons then pass the BDNF on to striatal neurons, which need BDNF to survive, but do not make their own supply.

In people with Huntington's, a lower level of wild-type huntingtin protein is produced, because the cortical cells are producing mutant as well as normal huntingtin. So a lower amount of normal, wild-type huntingtin protein is available in HD people to stimulate BDNF production in the cortex. In non-HD people, the wild-type huntingtin protein also helps transport BDNF from the cortex to the striatum, and this transport function is impaired in those who have Huntington's disease, too. In sum, BDNF levels in the striatum are low in those with HD, and striatal neurons are then damaged in the typical pattern of neurodegeneration seen in Huntington's disease.

The Canals studies show still more about BDNF — that the time of onset and severity of motor symptoms in model HD mice, as well as changes to the brain, are correlated with BDNF levels in the striatum. Lower BDNF levels are associated with more extreme motor deficits in HD mice. Furthermore, if model HD mice are given BDNF when the disease is just beginning to show (at disease onset), their striatal neurons suffer less degeneration, and the mice appear to show improvements in some motor function.

In reaching these findings, the researchers first looked at living cell cultures, discovering that the length (number of CAG repeats) and the level of mutant huntingtin protein found in a cell determine how much BDNF that cell produces. Then, the researchers carried out a genetic cross of wild-type mice and mutant Huntington's mice, on one hand, and wild-type mice and mice engineered to be BDNF-deficient, on the other. This genetic cross produces a "double mutant" mouse line, as seen in the table. (The types of mice crossed are shown on the table head and in the left table column, and the four types of offspring resulting are shown inside the table.)

	Wild-type huntingtin mice	Mutant huntingtin mice
Bdnf+/+ mice	Wild-type mice, with normal levels of the BDNF protein	Mutant huntingtin mice, with the normally reduced BDNF levels seen in HD
Bdnf+/- mice	Normal mice, with low levels of the BDNF protein	Mutant huntingtin mice, with extra-low BDNF levels

The mice carrying the mutant huntingtin gene that produced the lowest levels of BDNF (lower right cell of table) showed earlier and more severe motor deficits, and greater neurodegeneration of striatal tissue compared to mutant HD mice that produced a greater amount of BDNF (top right cell in table). Note that all the HD (mutant) mice in this study were genetically identical (all the mice in the entire right column), except for the difference in their BDNF levels. So the differences in their behavior and degree of neurodegeneration resulted from the differences in their BDNF levels.

The abstract of the Canals et al. (2004) paper is presented below; the full version is available free through this link to http://www.jneurosci.org/. Again, for more background on BDNF research and on how to raise BDNF levels, see the weblinks given above in the article.

-- Ann Covalt
Posted to the HDL: 11 Apr 2006

Brain-Derived Neurotrophic Factor Regulates the Onset and Severity of Motor Dysfunction Associated with Enkephalinergic Neuronal Degeneration in Huntington's Disease

JM Canals, JR Pineda, JF Torres-Peraza, M Bosch, R Martín-Ibañez, MT Muñoz, G Mengod, P Ernfors, and J Alberch

The mechanism that controls the selective vulnerability of striatal neurons in Huntington's disease is unclear. Brain-derived neurotrophic factor (BDNF) protects striatal neurons and is regulated by Huntingtin through the interaction with the neuron-restrictive silencer factor. Here, we demonstrate that the downregulation of BDNF by mutant Huntingtin depends on the length and levels of expression of the CAG repeats in cell cultures. To analyze the functional effects of these changes in BDNF in Huntington's disease, we disrupted the expression of bdnf in a transgenic mouse model by cross-mating bdnf+/ - mice with R6/1 mice. Thus, we compared transgenic mice for mutant Huntingtin with different levels of BDNF. Using this double mutant mouse line, we show that the deficit of endogenous BDNF modulates the pathology of Huntington's disease. The decreased levels of this neurotrophin advance the onset of motor dysfunctions and produce more severe uncoordinated movements. This behavioral pathology correlates with the loss of striatal dopamine and cAMP-regulated phosphoprotein-32-positive projection neurons. In particular, the insufficient levels of BDNF cause specific degeneration of the enkephalinergic striatal projection neurons, which are the most affected cells in Huntington's disease. This neuronal dysfunction can specifically be restored by administration of exogenous BDNF.

Therefore, the decrease in BDNF levels plays a key role in the specific pathology observed in Huntington's disease by inducing dysfunction of striatal enkephalinergic neurons that produce severe motor dysfunctions. Hence, administration of exogenous BDNF may delay or stop illness progression.

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Source: The Journal of Neuroscience, September 1, 2004, 24(35):7727-7739

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