Mouse Model of Huntington’s Disease Shows Replacement of Lost Neurons by Endogenous Stem Cell Populations

Huntington’s disease (HD) is a debilitating and invariably fatal disease that results from mutations in the IT15 gene. IT151 stands for “interesting transcript 15,” but it is more commonly referred to as the “huntingtin” gene. Mutations in the front of the gene (exon 1 for those who are interested) expand a run of CAG codons, and these mutations are probably the result of DNA polymerase slippage. Because CAG codons encode the amino acid glutamine, the mutant proteins contain long polyglutamine repeats and these repeats tend to clump inside neurons.

These protein aggregates form in neurons of the “striatum.” The striatum is a region of the brain that is also called the striate nucleus of the striate body. The striatum receives its name from the fact that it is organized in striped layers of gray and white matter. The striate nucleus is part of the cerebrum or forebrain.


Mutant Huntington (Htt) protein has a toxic that causes cell death by means of unknown mechanisms. Clinically, the most obvious symptoms of HD involve involuntary movements of the arms, legs, and face. But the severe cognitive and personality changes are the most devastating to HD patients and most troubling for their caregivers.

Researchers are using animal models of HD to study the disease pathogenesis, to elucidate areas of the brain involved in structural and functional decline, and to evaluate potential therapeutic interventions. These animal models include injecting toxins into the brain to kill off those populations of neurons that typically die in HD patients, and transgenic models in which animals are bred with either extra mutant copies of the Htt gene or a pair of copies of the mutant Htt gene that have replaced the original, normal copies. All of these model systems have limitations, but they are all useful in some way for assessing the pathology of HD.

This long introduction leads us to new data from the laboratory of Steve Goldman, the co-director of the University of Rochester Medical Center’s Center for Translational Medicine. Goldman and his colleagues triggered the production of new neurons in mice that had a rodent form of HD. These new neurons successfully integrated into the brain’s existing neural networks and dramatically extended the survival of the mice.

“This study demonstrates the feasibility of a completely new concept to treat Huntington’s disease, by recruiting the brain’s endogenous neural stem cells to regenerate cell lost the disease,” said Goldman.

One of the types of neurons most commonly affected in HD patients is the medium spinal neuron, which is critical to motor control. Goldman banked on findings from previous studies in his laboratory on canaries. Songbirds such as canaries have the ability to lay down new neurons in the adult brain when mating season comes. The male birds, in response to a flush of male sex hormones,, grow a gaggle of new neurons in the vocal control centers of the brain, and this provides the bird the means to sing specific songs in order to attract mates. This event is known as adult neurogenesis, and Goldman and Fernando Nottebohm of the Rockefeller University discovered this phenomenon in the early 1980s.

“Our work with canaries essentially provided us with the information we needed to understand how to add new neurons to adult brain tissue,” said Goldman. Once we mastered how this happened in birds, we set about how to replicate the process in the adult mammalian brain.”

Humans possess the ability to make new neurons, but Goldman’s lab demonstrated in the 1990s that a font of neuronal precursor cells exist in the lining of the ventricles (these are structures at the very center of the brain and spinal cord that are filled with cerebrospinal fluid). In early development, these cells are actively producing neurons.

Shortly after birth, the neural stem cells stop generating neurons and produce support cells called glia. Some parts of the human brain continue to produce neurons into adulthood, the most prominent example is the hippocampus, where memories are formed and stored. However, the striatum, new neuron production is switched off in adulthood.

Goldman sought to switch neuron production back on in the striatum. He tested a cadre of growth factors that would switch the neural stem cells of the striatum (a region that is ravaged by HD) from producing new glia to producing new neurons. Goldman, however, had some help from his recent work in canaries. Namely that once mating season was upon the birds, targeted expression of brain-derived neurotrophic factor (BDNF) flared up in the vocal centers of the brain, where many new neurons were being produced.

Goldman used genetically engineered viruses to express BDNF and another protein called “Noggin” in the striatum. Goldman and others found that a single intraventricular injection of the adenoviruses expressing BDNF and Noggin triggered the sustained recruitment of new neurons in both normal of R6/2 (HD) mice. These treated mice also showed that the newly formed neurons were recruited to form new medium spiny neurons; the ones destroyed in HD. These new neurons also matured and achieved circuit integration.

Medium Spinal Neuron
Medium Spinal Neuron

Also the treated mice showed delayed deterioration of motor function and substantially increased survival.

When the same experiments were conducted in squirrel monkeys, there was a similar addition of new striatal neurons.

Thus, induced neuronal addition may therefore represent a promising avenue for decreasing the ravages of HD and increasing cognitive ability.

Misfolded Protein Can Transmit Parkinson’s Disease from Cell to Cell

A research team led by Virginia Lee, who works as a neurobiologist at the University of Pennsylvania in Philadelphia has provided a mechanism for how misfolded proteins cause Parkinson’s disease. Lee’s group has resurrected an old treatment strategy that was discarded long ago that just might to slow the progression of this neurological disease.

Alpha-synuclein is a strange name for a protein, but it is a specifically found in the nervous system. Alpha-synuclein protein can compose as much as 1% of all the protein in the cytoplasm of a neuron. It is found all over the brain. What this protein actually does is a bit of a mystery, but the latest data suggests that alpha-synuclein helps traffic proteins from membranes to other places in the cell (Cooper et al., (2006). Science 313: 324–328).

In the brains of patients with Parkinson’s disease, neurons accumulate protein aggregates known as Lewy bodies. A major component of Lewy bodies is alpha-synuclein that has folded in an aberrant manner. These aggregations of misfolded alpha-synuclein cause a variety of problems inside cells that culminate in the death of the neuron.

This is the story of Parkinson’s disease so far, but Lee and her colleagues injected a misfolded synthetic version of α-synuclein into the brains of normal mice and saw the key characteristics of Parkinson’s disease develop and progressively worsen. While that is not a surprise, what Lee and co-workers found when they examined the brains of the injected laboratory animals astounded them. This study, which was published in the journal Science, shows that the injected misfolded alpha-synuclein was able to spread from one nerve cell to another. Therefore, the malformed protein did not just take up residence inside neurons, but instead was able to travel from one neuron to another.

Apparently, cells affected by misfolded alpha-synuclein are able to secrete it into the areas that surround them and this secreted protein is taken up by healthy cells. Once taken up, the misfolded alpha-synuclein induces the normal copies of the alpha-synuclein protein snap into the misfolded conformation. This eventually kills off the once-healthy neuron and also turns it into a new factory for the secretion of misfolded alpha-synuclein, which them goes on to damage other neurons.

This finding, however, raises the possibility that an antibody that binds the misfolded α-synuclein could potentially bind the protein and prevent it from passing between nerve cells. “It’s very hard to ask antibodies not only to get inside the brain, but to get inside cells,” says Lee. “But now you have the possibility of stopping the spreading. And if you stop the spreading, perhaps you can slow the progression of the disease.”

The tendency of the pathology of Parkinson’s disease to spread from neuron to neuron by a rogue protein was actually suggested in 2008. Fetal neural tissue transplants were used to treat Parkinson’s patients, but upon post-mortem examination of the transplanted fetal tissue, it was quickly recognized that these transplants has developed the characteristic Lewy bodies associated with Parkinson’s disease. This indicated that the nearby diseased cells were able to infect the transplanted tissue with Parkinson’s disease. Subsequent studies have shown that misfolded alpha-synuclein does spread between neighboring cells and induce cell death (Desplats, P. et al. Proc. Natl Acad. Sci. USA 106, 13010–13015 (2009).). The neurons, apparently, can release vesicles filled with misfolded alpha-synuclein in the same way they release neurotransmitters. This release bathes the nearby cells in misfolded alpha-synuclein, but there are still questions as to whether or not the misfolded alpha-synuclein is responsible for the cascade of brain damage seen in Parkinson’s.

Lee says that her team has now captured the full consequences of runaway α-synuclein in the brain. “We knew this transfer from one cell to another can happen, but whether it could play a significant role in the disease was still open,” says Tim Greenamyre, director of the Pittsburgh Institute for Neurodegenerative Diseases in Pennsylvania, who was not involved in the latest work.

Besides Lewy bodies, the brains of patients with Parkinson’s disease also show a dramatic loss of those neurons that produce the chemical messenger dopamine. When Lee’s team injected the misfolded α-synuclein into a part of the mouse brain rich in dopamine-producing cells, Lewy bodies began to form, followed by the death of dopamine neurons. Nerve cells linked to those near the injection site also developed Lewy bodies, which showed that cell-to-cell transmission was occurring.

Greenamyre says that is possible, but hasn’t yet been proved. “All of the cells affected in this paper were those directly in contact with the injection site,” he says. But, within six months of the injection, coordination of movement, grip strength and balance had all deteriorated in the mice, which is a recapitulation of what occurs in people with Parkinson’s disease.

“It’s really pretty extraordinary,” says Eliezer Masliah, a neuroscientist at the University of California, San Diego. “We have been trying that experiment for a long time in the lab and we have not seen such dramatic effects.” According to Masliah, Lee’s work provides the impetus for that handful of biotechnology companies that are sponsoring clinical trials of alpha-synuclein antibodies for as therapeutic agents for Parkinson’s disease. Masliah hopes that this will also motivate neuroscientists to examine exactly how the protein enters and exits cells.

There is still one mystery that has not been addressed to data: why do the Lewy bodies appear in the first place? “Parkinson’s disease is not a disorder in which somebody injects synuclein into your brain,” notes Ted Dawson, director of the Institute for Cell Engineering at Johns Hopkins University in Baltimore, Maryland. “So what sets it in motion?” Clearly some mutations in the gene that encodes alpha-synuclein increase the tendency for this protein to spontaneously misfold. But this also suggests that there are particular triggers that lead to such events. The nature of these triggers will certainly be the subject of future work.