New Huntington’s disease model hints at novel therapeutic target

Mature neuron

Neurodegenerative diseases like Huntington’s (HD) have lacked effective therapy, in part due to the difficulty in recapitulating the disease in a laboratory setting. Now a team of scientists has created a new model of HD and in doing so, discovered a protein subunit that may reverse the disease model.

Senior author William Mobley from the UC San Diego School of Medicine and his team published their work in the journal PNAS earlier this week.

The researchers combined two key types of neurons--cortical neurons and striatal neurons--from a mouse model of HD in a microfluidics chamber. This "co-culture" experiment allowed them to connect the two neurons, resembling what happens in the human brain.

The two neuron types make up the corticostriatal pathway, which classically degenerates in patients with HD and patients subsequently present with the HD symptoms, including impaired memory, thought, language, consciousness, behavior and movement, among others.

"The new model and the ability to recreate the abnormal circuit is more physiologically relevant than many other models, " said Xiaobei Zhao, first author of the study, in a statement. "Most important, it facilitates study of disease mechanisms and possible new disease-modifying treatments.”

They found that dysfunctional cortical neurons drive the subsequent dysfunction of striatal neurons through the reduced signaling of a growth factor called BDNF. They also discovered a protein subunit of the TRiC protein that could rescue the degeneration of the striatal neurons by inhibiting aggregates of the mutant huntingtin proteins (the abnormal protein product from the genetic mutation in the huntingtin gene, HTT).

"Importantly, using this model provided evidence that expression of a single subunit of the TRiC protein, which inhibits the aggregation of mutant huntingtin proteins, rescued atrophy of striatal neurons,” said Zhao in the statement. "The next step is to test this in vivo. If the phenotype of the HD mouse model can be rescued, it's possible that TRiC could be used to treat Huntington's disease."