Scientists discover new cause and potential treatment target for Huntington’s disease

Researchers have identified a groundbreaking link between the CHCHD2 gene and Huntington’s disease (HD), a genetic neurodegenerative disorder. For the first time, this gene has been implicated as a factor in HD and offers a potential target for treatment.

Conducted by teams from the Max Delbrück Center and Heinrich Heine University Düsseldorf (HHU), the study represents a step forward in understanding HD and its progression. By revealing previously unknown effects of Huntington gene (HTT) mutations on mitochondrial health and brain development, the findings open a pathway to exploring early interventions in the disease.

Huntington’s disease is a rare, incurable disorder affecting approximately five to 10 in every 100,000 people globally. The disease results from a genetic mutation in HTT, leading to an excessive repetition of three nucleotides—cytosine, adenine, and guanine (CAG)—in the gene sequence.

While a person with 35 or fewer CAG repeats is generally safe from the disease, those with 36 or more are at risk, with symptoms developing sooner as the number of repeats increases. Over time, HD causes nerve cells in the brain to die, resulting in loss of muscle control and psychiatric issues, such as delusions and hallucinations. Although current therapies address the symptoms, they do not slow the disease’s progression or provide a cure.

The new study, published in Nature Communications, combined efforts from six different labs. Dr. Jakob Metzger from the “Quantitative Stem Cell Biology” lab at the Max Delbrück Center and Professor Alessandro Prigione’s “Stem Cell Metabolism” lab at HHU led the research. These labs harnessed their expertise in Huntington’s disease, brain organoids, and gene editing to investigate the disease’s roots.

“We were surprised to find that Huntington’s disease can impair early brain development through defects associated with mitochondrial dysfunction,” said Dr. Pawel Lisowski, co-lead author from Metzger’s lab. He highlighted that the study sheds light on how mitochondrial damage from HTT mutations affects brain health even before HD symptoms emerge.

A key tool in this research was the use of brain organoids, three-dimensional structures grown from stem cells that mimic human brain tissue. These organoids provide an unparalleled look at cell interactions, giving researchers a model to understand diseases in ways previously unachievable in laboratory settings. As organoids can be created from various tissues depending on the research question, they serve as an ideal model for investigating neurological disorders like HD.

Through the organoid model, researchers found that HTT mutations lead to underexpression of the CHCHD2 gene, which is critical for maintaining mitochondrial health. CHCHD2 had been linked to Parkinson’s disease but was previously unassociated with HD.

“The organoid model suggests that HTT mutations damage brain development even before clinical symptoms appear,” added Selene Lickfett, co-lead author and a doctoral student at HHU, underscoring the potential for early detection. Her observations indicate that disease progression may start well before it becomes clinically apparent, highlighting a need for earlier diagnostic measures.

Moreover, restoring CHCHD2 function in these models reversed some effects on neurons. This reversal suggested that CHCHD2 could serve as a target for HD therapies, said Lickfett. “That was surprising. It suggests in principle that this gene could be a target for future therapies.”

This finding represents a significant shift from the conventional view of HD as a disease that affects mature neurons in the brain. Instead, it may point to a developmental origin, with neuronal changes occurring much earlier in life than previously thought.

In addition to observing developmental anomalies in neural progenitor cells and organoids, researchers noted that these defects occurred before the presence of toxic aggregates of the mutated Huntingtin protein. Typically, HD pathology is associated with these protein clumps, which accumulate as the disease progresses. According to Metzger, the discovery that cellular damage appears even before these aggregates form further emphasizes the potential need for early intervention.

“The prevalent view is that the disease progresses as a degeneration of mature neurons,” said Prigione. “But if changes in the brain already develop early in life, then therapeutic strategies may have to focus on much earlier time-points.” By uncovering these earlier developmental effects, Prigione’s team has paved the way for a new perspective on HD treatment. If therapies can be developed to target these changes in early life, it could potentially transform the approach to managing HD.

The process of modifying the HTT gene for study proved challenging due to the repetitive nature of the CAG sequence in the gene. Lisowski explained that conventional gene-editing tools often struggle with sequence repeats, which limited the team’s options.

They used advanced Cas9-based gene-editing technology and DNA repair pathway manipulation to alter healthy induced pluripotent stem cells, introducing an expanded CAG repeat section in the HTT gene to replicate HD. The genetically modified cells were then cultivated into brain organoids, creating models with characteristics similar to early-stage human brains affected by HD.

Gene editing remains an area of keen interest, as the team’s success in reversing certain developmental defects using CRISPR-based methods suggests that similar strategies may someday prove viable in clinical settings. “Our genome editing strategies, in particular the removal of the CAG repeat region in the Huntington gene, showed great promise in reversing some of the observed developmental defects. This suggests a potential gene therapy approach,” said Prigione, hinting at the future possibilities of genetic intervention.

Increasing CHCHD2 expression represents another potential therapeutic route, given its role in mitochondrial function. As CHCHD2 is essential for cellular energy production, interventions targeting its expression could counteract mitochondrial damage caused by HTT mutations.

Researchers are hopeful that manipulating this pathway could yield benefits not only for HD but also for other neurodegenerative diseases involving mitochondrial dysfunction. “Early treatments that reverse the mitochondrial phenotypes shown here could be a promising avenue for counteracting age-related diseases like Huntington’s disease,” Prigione added.

Huntington’s disease is part of a group of neurodegenerative disorders associated with gene mutations that disturb normal brain development and function. Although the mechanisms behind these diseases are not yet fully understood, evidence suggests HD may affect brain development much earlier than previously thought.

For example, studies on mice have shown that HTT disruption can be lethal during embryonic stages and can hinder brain development if silenced in specific brain regions. Similar findings in human fetuses carrying HTT mutations align with the mouse data, indicating that HD impacts brain development before typical symptom onset.

By identifying CHCHD2 as a contributor to HD, the study highlights the potential to address the disease at an earlier stage. When combined with gene-editing approaches to remove or adjust harmful mutations, this discovery offers a promising avenue for therapeutic development.

The research also underscores the broader implications for other neurodegenerative diseases, with potential early interventions targeting mitochondrial health and brain development.

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