New Look at Gene Expression in the Brain May Offer Clue to Treating Huntington's Disease

New research conducted by scientists from Lund University in Sweden is shedding new light on Huntington’s disease and the potential for new therapies for this and other neurodegenerative diseases.

The progressive brain disorder, Huntington’s disease (HD), typically has an onset in adulthood and is marked by uncontrolled movements, emotional problems, and cognitive loss. The condition is caused by mutations in the HTT gene, which provides instructions for the production of a protein called huntingtin that plays an important role in the brain’s nerve cells. This mutation leads to a buildup of protein aggregates in the nerve cells of the brain, thereby impairing their normal functions.

Autophagy is the biological process by which nerve cells break down and remove protein aggregates, a process which is disrupted in individuals with neurodegenerative diseases (NDDs), such as HD, Parkinson’s, and Alzheimer’s. In a recent study published in the journal Cell Reports, investigators set out to find if activating the process of autophagy can reverse the accumulation of the protein Argonaute-2 (AGO2) in neurons.

“We know very little about why protein aggregates arise or in what way they are involved in the development of the disease,” said the study’s lead author and head of the university’s Molecular Neurogenetics Jakobsson Lab, Johan Jakobsson, PhD, in a recent statement. “However, our study shows that expression of the mutated huntingtin gene impairs the nerve cells’ ability to break down and recycle cellular material, which results in an accumulation of the protein AGO2.”

By studying cell culture, mouse models, and human tissue from deceased HD patients, the investigators observed that AGO2 accumulation results in an increase in levels of microRNA (miRNA) levels, and that changes in the autophagy mechanism also resulted in extensive changes in microRNA activity. Their findings, according to the authors, indicate that impaired autophagy in Huntington’s disease and other diseases not only effects protein aggregation but also “directly contributes to global alterations of intracellular post-transcriptional networks.”

“Our study indicates that changes in miRNA levels are an early sign of Huntington’s disease and are a result of changes in autophagy,” researcher Karolina Pircs, PhD, said. “It shows a direct link between protein aggregation and gene regulation.”

The findings are just one step toward the development of a novel therapy, say the authors. “Our data also provide further support for developing autophagy-activating therapeutic approaches for HD and other NDDs because they suggest that activation of autophagy will not only clear toxic protein aggregates but also directly restore dysfunctional post-transcriptional gene regulation,” they conclude in their study.

In another study published earlier this year, researchers in Germany identified how a ubiquitin ligase protein called UBR5 plays a key role in protecting cells and encouraging the degradation of mutant huntingtin. Other recent research into treating HD has focused on silencing the mutated gene causing the condition, the use of drugs typically used to treat other ailments, as well as immunotherapy.