Huntington disease is a horrible, slow, relentless and progressive death sentence. This disease is inherited, and if one of your parents has Huntington’s disease (HD), you have a 50% chance of inheriting the disease. HD is cause by mutations in a gene found on human chromosome 4. This mutation resides in a gene that encodes the Huntingtin protein. However, these mutations are unusual in that they are due to excessive number of repeats of the triplet sequence, CAG. CAG codes for the amino acid glutamine, and normally, there is a stretch of 10-28 glutamines in normal versions of the Huntingtin protein. However, CAG repeats tend to cause the enzymes that make DNA to slip and resynthesize the repeat, thus causing the number of consecutive CAG triplets in this gene to expand. In persons with Huntington’s disease, the CAG triplet is repeated anyways from 36 to 120 times. This expands the stretch of glutamine residues and creates and toxic protein that is cut into smaller fragments that kill nerve cells.
The symptoms of Huntington’s disease usually begin with behavioral disturbances that show up before the onset of movement disorders. These behavioral symptoms can include hallucinations, irritability, moodiness, restlessness or fidgeting, paranoia, and even psychosis. Abnormal movements begin and these include facial movements, including grimaces, the turning of the head to shift eye position rather than moving the eyes, quick, sudden, sometimes wild jerking movements of the arms, legs, face, and other body parts, slow, uncontrolled movements, and an unsteady gait. The dementia slowly gets worse and other symptoms eventually emerge that include disorientation or confusion, loss of judgment, loss of memory, personality changes, and speech changes.
This disease has no treatments and no cure, but researchers have published a paper in the journal Cell Stem Cell that is a starting block of further research that might lead to a treatment. In this paper, a special type of brain cell generated from stem cells seems to help ameliorate the muscle coordination deficits that eventually lead to uncontrollable spasms (choreas) that are so characteristic of the disease.
Su-Chun Zhang, a neuroscientist at the University of Wisconsin-Madison and senior author of the new study said: “This is really something unexpected.” This work suggests that locomotion could be restored in mice with a Huntington’s-like condition.
Zhang’s laboratory has a great deal of experience and expertise at making different types of brain cells from human embryonic stem cells or induced pluripotent stem cells. In the newly published article, Zhang and his colleagues reported the production of neurons that use a neurotransmitter called “gamma-amino butyric acid,” which thankfully goes by the acronym “GABA.” GABA is one of the most heavily used neurotransmitters in the central nervous system, and GABA receptors come in many shapes and sizes, but virtually all of them are chloride channels. While this may not mean anything to you, to a neuron that is trying to generate a nerve impulse, chloride ions are inhibitory and they cut the neuron off at the knees. GABA, therefore, is an extremely important inhibitory neurotransmitter that shuts neurons down when they need to be shut down.
This significance of making GABA-using neurons in the laboratory cannot be lost on Huntington’s patients, because GABA-making neurons are the ones that take the biggest beating during the onset of Huntington’s disease. Without these GABA-using neurons, it is impossible for various portions of the brain to properly coordinate movement. According to Zhang, GABA-producing neurons produce one the key neurotransmitters for coordinating movement.
At the UW-Madison Waisman Center, Zhang and his colleagues discovered how to make large quantities of GABA neurons from human embryonic stem cells. They then tested these neurons in mice that had an induced condition that resembled Huntington’s disease. They implanted these cells in the brains of mice, and they were very surprised to see that the implanted cells not only integrated into the brain, but also projected axons to the correct targets and effectively reestablished the broken communication network. This largely restored motor function.
Zhang noted that these results surprised so because GABA-making neurons are found in a part of the brain called the basal ganglia. The basal ganglia play a central role in voluntary motor coordination. However, GABA-making neurons, however, exert their influence at a distance on cells in the midbrain through neural circuits that are fueled by the GABA-making neurons.
Zhang explained it this way: “This circuitry is essential for motor coordination, and it is what is broken in Huntington patients. The GABA neurons exert their influence at a distance through this circuit. Their cell targets are far away.”
Zhang, however, did not stop there. Many neuroscientists do not think that the results Zhang and his co-workers observed are even possible. He explained further: “Many in the field feel that successful cell transplants would be impossible because it would require rebuilding the circuitry. But what we’ve shown is that the GABA neurons can remake the circuitry and produce the right neurotransmitter.”
This new study has profound implications for regenerative therapy of neurodegenerative disease. One day, it might be possible to treat Huntington’s disease with cell transplants that capitalize on the plasticity of the adult brain. Zhang noted that the adult brain is considered by some neuroscientists to be stable and not easily susceptible to therapies that try to correct things like broken neural circuits. For a therapy to work, it has to be engineered so that it targets only specific cells. Zhang added, “The brain is wired in such a precise way that if a neuron projects the wrong way, it could be chaotic.”
This new research is indeed promising, but it must be worked up and correlated from the mouse model to the condition found in human patients, and this type of very hard, tedious work will take a great deal of time, people hours, and a whole lot of trial and error. However, for a disease that now has no effective treatment, this work could become the next best hope for Huntington’s disease patients.
A caveat to this research is that the mice with Huntington’s disease-like symptoms were given the disease by means of the chemical called quinolinic acid. Administration of this chemical by means of “bilateral intrastriatal microinjections,” which is a fancy way of saying injecting really small amounts of this stuff into a specific part of the basal ganglia, generates mice that display the movement disorders similar to those seen in humans with this disease (see Sanberg PR, et al., Experimental Neurology 1989 Jul;105(1):45-53). Also, the pathology of the brains of these mice shows some similarity to that observed postmortem in the brains of Huntington’s disease patients.
The problem is this: implanting cells into the brains of mice that have been subjected to quinolinic acid results in those cells living and taking up residence in the brain of the mouse and somewhat reconstructing the striatum of the mouse brain (see Dunnett SB. Novartis Found Symp. 2000;231:21-41; discussion 41-52). This is due to the fact that quinolinic acid lesions in the brain specifically kill off particular parts of the brain, but the environment of the brain is still relatively normal. When similar experiments are attempted in human patients, the implanted tissue takes a beating and dies because the brains of Huntington’s disease patients are not chemically altered, but genetically altered. These brains are a toxic waste dump, so to speak, and implanted tissue or cells die (see Francesca Cicchetti, Denis Soulet, and Thomas B. Freeman. “Neuronal degeneration in striatal transplants and Huntington’s disease: potential mechanisms and clinical implications,” Brain (2011) 134 (3): 641-652. doi: 10.1093/brain/awq328).
It seems to me that the environment of the brain must be improved before cell therapy is going to work, and that is a much more difficult problem to address. Dying neurons spill their neurotransmitters into the intracellular space. Huge neurotransmitter overdose can kill nearby neurons and this contributes to the toxic environment in the brain of Huntington’s disease patients. Finding a way to quell the poisonous products released by dead neurons is the next great unanswered quest for these patients.