Promising new drug target identified for Huntington's disease

New research targeting a glutamate transporter protein has produced a “quite remarkable” reversal of Huntington’s disease symptoms in laboratory mice.

University of Ottawa (uOttawa) scientists restored normal cognitive and motor function after breeding ‘knockout’ mice lacking the VGLUT3 protein with mice carrying the disease-causing mutant huntingtin gene.

The results provide researchers with a promising target for a drug capable of treating humans who suffer from Huntington’s – a disease that affects around one in every 10,000 people but currently has no cure. 

“We saw a complete reversal of Huntington disease progression in mutant huntingtin mice lacking VGLUT3,” said Professor Stephen Ferguson, from uOttowa’s Faculty of Medicine.

“From 6 to 15 months of age, the knockout mice behaviorally were indistinguishable from wild-type mice, whereas the Huntington's mice continued to be more and more impaired over time on the various motor behavior and cognitive tasks that we tested on.”

Writing in The Journal of Neuroscience, the uOttawa researchers said they investigated VGLUT3 because Huntington’s disease develops after “evident impairment in glutamatergic neurotransmission leading to severe striatal neurodegeneration”, and since VGLUT3 “regulates the striatal network that is centrally affected by HD (Huntington’s).”

After crossing mice lacking Slc17a8 gene (VGLUT3^–/–) with the heterozygous zQ175 knock-in mouse model of HD (zQ175:VGLUT3^–/–), they monitored their offspring’s performance in a series of behavioural experiments conducted by report lead author Dr Karim Ibrahim - including rotarod, novel object recognition, grip strength and horizontal ladder tests.

Encouragingly, results from the novel object recognition test indicated that the deletion of VGLUT3 can rescue memory deficits in HD mice – since “zQ175 mice of both sexes were not able to discriminate between novel and familiar objects” at 12 and 15 months of age, whereas zQ175:VGLUT3–/– mice of both sexes showed improved recognition indices for the novel objects at the same ages.

Meanwhile, the group “detected an age-dependent deterioration in the rotarod performance for both male and female zQ175 mice”, whereas “Double mutant mice demonstrated improved rotarod performance in both male and female mice at all ages to levels that were indistinguishable from age- and sex-matched WTs (wild-type mice).” The performance of the double mutant mice was also superior to their zQ175 counterparts in both the grip strength and horizontal ladder tests – indicating that “VGLUT3 deletion does not impair motor functions in healthy mice but rescues deficits in limb coordination and grip force in zQ175 HD mice.”

The group was also able to demonstrate through immunostaining techniques that VGLUT3 deletion prevented the striatal neuronal loss associated with Huntington’s. They noted “a significant decrease in the number of NeuN-labeled  (immunostained) neurons” in 15-month-old male and female zQ175 mice, compared with age- and sex-matched WTs. However, the same loss was not observed in zQ175 mice with the VGLUT3 deletion.

The sole symptom progression that deleting VGLUT3 failed to reverse in the mice was anxiety behaviour. The uOttawa group believe this may be because the protein has been shown to be involved in regulating conditions such as eating disorders and drug addiction – and so is also likely to affect anxiety and depression.

Another puzzle the group now hopes to solve is targeting the huntingtin gene in the striatum without interfering with its vital role in other body tissues. They are therefore working on suppressing VGLUT3 pharmacologically in ways that alter glutamate release in specific subsets of neurons.

“You don't really want to knock down the wild-type copy of the huntingtin gene if you can avoid it because the huntingtin protein is absolutely essential,” said Professor Ferguson.

“You're better off finding a way of tricking the brain into using its circuitry slightly differently so that you can re-establish motor coordination.

“We've shown that if you block glutamate release through the activation of presynaptic receptors, you can get an amelioration of Huntington's disease. So it may be that it will eventually require two or three different drugs to effectively treat the disease.”