Recent research led by a University of Ottawa Faculty of Medicine team is providing compelling insights into the mechanisms underlying the progression of Huntington’s disease in an animal model. The outcomes could lead on to a greater understanding of the harrowing neurological disease in humans and help pave the way in which for viable drug targets and treatment approaches.

That is potentially very significant because there are presently no drugs to slow or stop the progression of the genetic brain disorder that happens at a rate of about 1 in every 10,000 people. Huntington’s disease (HD) progressively breaks down neurons in areas of the brain, progressively ravaging a patient’s mind and spurring involuntary movements until victims are unable to walk, communicate, and even swallow. It may well be passed from parent to child, typically becoming evident in middle age.

The study, published today within the June 7 edition of the Journal of Neuroscience, focuses on a transporter protein known as VGLUT3. Within the brain, this tiny protein packages glutamate into vesicles for release from neurons. Glutamate is an excitatory neurotransmitter that’s involved in probably the most complex brain circuits. There must be a balance of glutamate to your brain to operate properly; an excessive amount of of it’s related to Huntington’s and other neurological ailments.

Over the span of years, researchers led by Dr. Stephen Ferguson discovered that VGLUT3 plays a surprisingly vital role in modulating the event of Huntington’s disease within the gold-standard mouse model. They bred so-called “knockout” mice that lack the transporter protein with mutant “huntingtin” mice so that they could run comparisons to unveil animal models of the rare disease in each female and male mice.

Individuals diagnosed with Huntington’s disease accumulate a particular mutated type of the “huntingtin” protein. This scaffolding protein is present in cells throughout the body, however the genetic defect that produces a mutant version appears to only impact the brain. The mutant triggers cell death.

Results showing the disease-modifying capability of the VGLUT3 transporter protein were “quite remarkable,” says Dr. Ferguson, a outstanding professor on the uOttawa Faculty of Medicine’s Department of Cellular and Molecular Medicine and Distinguished Research Chair in Neurodegeneration.

We saw an entire reversal of Huntington disease progression in mutant huntingtin mice lacking VGLUT3. From 6 to fifteen months of age, the knockout mice behaviorally were indistinguishable from wild-type mice, whereas the Huntington’s mice continued to be increasingly impaired over time on the assorted motor behavior and cognitive tasks that we tested on.”

Dr. Stephen Ferguson, outstanding professor on the uOttawa Faculty of Medicine’s Department of Cellular and Molecular Medicine and Distinguished Research Chair in Neurodegeneration

The one aspect of the symptom progression that did not show reversal within the mouse model was anxiety behavior. But this too could prove significant since the transporter protein – which has been shown to manage conditions reminiscent of eating disorders and drug addiction – is probably going also involved in anxiety and depression.

One among the paper’s reviewers described the general results as a “substantive contribution” that “must be of wide interest to researchers in HD in addition to those studying the role of VGLUT3 in cognition and motor control.”

The rigorous uOttawa-led study was also chosen to be highlighted in a special feature section of the Journal of Neuroscience, a peer-reviewed journal that publishes papers on a variety of topics of interest to those working on the nervous system.

The publication’s first creator is Dr. Karim Ibrahim, a member of Dr. Ferguson’s lab who’s a newly minted PhD at uOttawa. In recent times, he methodically conducted a variety of behavioral experiments to generate the study’s data. This included rotarod tests – certainly one of the classic tests of motor skills in mice – and a horizontal ladder test that clearly exposed a number of the impairments within the Huntington’s mouse model because the animals tried to traverse it.

Efforts to develop drug targets and treatment approaches for HD must take into accounts that the “huntingtin” protein is widely expressed within the body.

“You do not really need to knock down the wild-type copy of the huntingtin gene in case you can avoid it since the huntingtin protein is completely essential. You are higher off finding a way of tricking the brain into using its circuitry barely in another way so that you may reestablish motor coordination,” Dr. Ferguson says.

Ultimately, that is the goal for his lab and its collaborators of their Huntington’s disease efforts. They’re working on a toolkit for the pharmacological suppression of the VGLUT3 protein and exploring ways of doubtless altering glutamate release in specific subsets of neurons.

“We have shown that in case you block glutamate release through the activation of presynaptic receptors, that you may get an amelioration of Huntington’s disease. So it might be that it’s going to eventually require two or three different drugs to effectively treat the disease,” he says.

Collaborating with Dr. Ferguson’s lab on this study was Dr. Saleh El Mestikawy, a professor at McGill University’s Department of Psychiatry and a researcher on the Douglas Research Centre in Montreal.

Funding for the research work was provided by the Huntington Society of Canada and the Canadian Institutes of Health Research (CIHR).

Source:

Journal reference:

Ibrahim, K. S., et al. (2023) VGLUT3 deletion rescues motor deficits and neuronal loss within the zQ175 mouse model of Huntington’s disease. Journal of Neuroscience. doi.org/10.1523/JNEUROSCI.0014-23.2023.