Researchers have identified a new gene that may play a role in the development of Huntington’s disease using a brain organoid model. This gene could be linked to brain abnormalities appearing sooner than previously believed.
In a groundbreaking discovery, researchers have found that the gene CHCHD2 is associated with Huntington’s Disease (HD)—a genetic neurodegenerative condition that currently has no cure. The study suggests that CHCHD2 may serve as a new target for potential therapies. Using a brain organoid model for their research, the team observed that mutations in the Huntington gene HTT also impact CHCHD2, which plays a critical role in maintaining mitochondrial function. This work has been published in “Nature Communications.”
Six different research laboratories at the Max Delbrück Center collaborated on this study, under the direction of Dr. Jakob Metzger from the “Quantitative Stem Cell Biology” lab and Professor Alessandro Prigione’s “Stem Cell Metabolism” lab at Heinrich Heine University Düsseldorf (HHU). Each lab brought its specific expertise in areas such as Huntington’s disease, organoid development, stem cell studies, and genome editing. Dr. Pawel Lisowski, a co-lead author from the Metzger lab, noted, “We were surprised to find that Huntington’s disease can impact early brain development due to issues related to mitochondrial dysfunction.”
Furthermore, Selene Lickfett, another co-lead author and a PhD student in Prigione’s lab, added, “The organoid model indicates that HTT mutations may hinder brain development even before clinical symptoms emerge, emphasizing the need for early detection of this late-onset neurodegenerative disease.”
Understanding the unusual triplet repeat
An organoid refers to a three-dimensional, organ-like structure grown in laboratory settings using stem cells. These organoids can be developed from various tissue types depending on the disease being studied. Although only a few millimeters in size, they provide a unique model for understanding how different cell types interact. No other laboratory model offers such an intricate view of human cellular functions.
Huntington’s disease arises from excessive repetitions of the nucleotides Cytosine, Adenine, and Guanine in the HTT gene. Typically, individuals with 35 or fewer repeats do not face a risk of developing the disease, whereas those with 36 or more repeats are at risk. The likelihood of developing symptoms increases with the number of repeats, explains Metzger, a senior author of the study. The mutations lead to the progressive death of brain nerve cells, resulting in a gradual loss of muscle control and various psychiatric symptoms such as impulsivity, delusions, and hallucinations. Around five to ten individuals in every 100,000 are affected by Huntington’s disease worldwide. Current treatments only address symptoms but do not halt the disease’s progression or offer a cure.
The complexities of editing the HTT gene
To explore how mutations in the HTT gene influence early brain development, Lisowski employed variants of the Cas9 gene editing technology alongside modifications to DNA repair processes to alter healthy induced pluripotent stem cells, granting them a higher number of CAG repeats. This endeavor faced technical hurdles since gene editing tools are not very effective on gene regions with repetitive sequences, such as the CAG repeats found in HTT, according to Lisowski.
The modified stem cells were subsequently developed into brain organoids that mimic early-stage human brains. Upon analyzing the gene expression of these organoids at various developmental stages, researchers consistently found that the CHCHD2 gene was underrepresented, which negatively affected neuronal metabolism. While CHCHD2 has been linked to Parkinson’s disease, it had not been previously connected to Huntington’s disease.
They also discovered that restoring the CHCHD2 gene function could reverse adverse effects on neuronal cells. “This was unexpected,” says Selene Lickfett. “It implies that this gene could potentially be a target for future therapies.”
Moreover, the issues in neural progenitor cells and brain organoids were observed before any harmful aggregates of the mutated Huntingtin protein formed, according to Metzger, suggesting that the brain’s disease processes may begin far earlier than what is clinically evident.
Dr. Prigione remarked, “The common belief is that the disease progression is due to the degeneration of mature neurons, but if changes in the brain occur early in life, we may need to consider therapeutic interventions at much earlier stages.”
Implications for therapy
“Our genome editing methods, especially the removal of the CAG repeat region in the Huntington gene, showed significant promise in reversing some of the developmental issues observed. This indicates a potential gene therapy route,” Prigione notes. He also mentions that increasing CHCHD2 gene expression could be another therapeutic strategy.
The insights gained could also extend to other neurodegenerative illnesses, Prigione suggests, stating, “Early interventions that rectify the mitochondrial profiles observed here could represent a promising strategy to combat age-related diseases like Huntington’s disease.”
