Blocking Certain Glutamate Receptors Seen to Ease Huntington’s Advance in Mouse Model of Disease

Blocking Certain Glutamate Receptors Seen to Ease Huntington’s Advance in Mouse Model of Disease

Blocking specific glutamate receptors was seen to improve cellular, motor, and cognitive skills in a mouse model of Huntington’s disease.

The study, “mGluR5 antagonism increases autophagy and prevents disease progression in the zQ175 mouse model of Huntington’s disease,” appeared in the journal Science Signaling.

Glutamate is the main excitatory neurotransmitter in the brain. Metabotropic glutamate receptor 5 (mGluR5) is produced at high levels in those brain regions most affected by Huntington’s.

Previous research suggested that, similar to diseases such as Parkinson’s or depression, targeting mGluR5 could be a relevant in Huntington’s as genetic deletion or injection of an mGluR5 blocker was seen to reduce disease severity in mice.

Mutant huntingtin, responsible for Huntington’s disease, interacts with mGluR5 and proteins that regulate autophagy — a system that degrades cellular debris, including proteins. Although research shows that autophagic removal of toxic huntingtin aggregates is mediated by a protein receptor of the same superfamily as mGluR5, scientists still don’t know the identity of the specific receptor.

Canadian researchers used a genetic mouse model that mimics Huntington’s disease, and treated the animals with CTEP, an mGluR5 blocker, for 12 weeks.

The study showed that treating both heterozygous and homozygous (where both or only one gene copy is defective, respectively) mice with CTEP decreased the size and number of huntingtin aggregates and neuronal death in the brain.

CTEP also improved motor (locomotor activity, grip strength and motor coordination) and cognitive skills (new object recognition). These results point to a potential for mGluR5 blockers “slowing and reversing disease progression in zQ175 mice,” the researchers wrote.

Of note, improvements in motor function of the homozygous mice (with more severe impairment before treatment) were not as complete as those of heterozygous mice. Similarly, CTEP was seen to improve memory in heterozygous, but not homozygous, mice.

Data also showed that the reduction in huntingtin aggregates correlated with activation of both a newly identified autophagy pathway and a classical autophagic pathway for the production of autophagosomes — cellular structures that contain the cellular material to be degraded.

Compared to previous approaches to activate authopagy, CTEP showed superior ability to cross the blood-brain barrier (and reach higher levels in the brain) and did not induce relevant side effects, the researchers observed.

Overall, “the findings suggest that mGluR5 antagonism may activate autophagy through convergent mechanisms to promote the clearance of mutant huntingtin aggregates and might be therapeutic in HD patients,” they concluded.

José is a science news writer with a PhD in Neuroscience from Universidade of Porto, in Portugal. He has also studied Biochemistry at Universidade do Porto and was a postdoctoral associate at Weill Cornell Medicine, in New York, and at The University of Western Ontario in London, Ontario, Canada. His work has ranged from the association of central cardiovascular and pain control to the neurobiological basis of hypertension, and the molecular pathways driving Alzheimer’s disease.
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José is a science news writer with a PhD in Neuroscience from Universidade of Porto, in Portugal. He has also studied Biochemistry at Universidade do Porto and was a postdoctoral associate at Weill Cornell Medicine, in New York, and at The University of Western Ontario in London, Ontario, Canada. His work has ranged from the association of central cardiovascular and pain control to the neurobiological basis of hypertension, and the molecular pathways driving Alzheimer’s disease.
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José is a science news writer with a PhD in Neuroscience from Universidade of Porto, in Portugal. He has also studied Biochemistry at Universidade do Porto and was a postdoctoral associate at Weill Cornell Medicine, in New York, and at The University of Western Ontario in London, Ontario, Canada. His work has ranged from the association of central cardiovascular and pain control to the neurobiological basis of hypertension, and the molecular pathways driving Alzheimer’s disease.

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