SCA7 is a rare inherited neurodegenerative disorder that gradually damages nerve cells responsible for movement, balance, coordination, and vision. This disease follows an autosomal dominant pattern of inheritance, meaning that inheriting just one altered copy of the ATXN7 gene from either parent is enough to develop the disease. The age at which symptoms begin can vary widely, from infancy to late adulthood, and is largely influenced by the number of repeated DNA sequences, called “CAG” repeats, within the ATXN7 gene.

Genes act as instruction manuals that tell our cells how to make proteins. In people with SCA7, the ATXN7 gene contains too many CAG repeats, leading to the production of an abnormal Ataxin-7 protein. This faulty protein gradually damages brain cells, particularly those in the cerebellum, which coordinates movement and balance, and the retina, which is essential for vision. Although researchers understand the genetic cause of SCA7, there is currently no treatment that can slow or stop disease progression. To develop effective therapies, scientists first need to understand how this genetic mutation damages brain cells.

Much of the previous research has focused on neurons, the cells responsible for transmitting information throughout the brain. However, neurons rely heavily on neighboring support cells called astrocytes. Astrocytes help maintain a healthy environment, provide nutrients, regulate communication between neurons, and support their energy needs. This study asked an important question: Could problems in astrocytes also contribute to the progression of SCA7?

To investigate this, the researchers collected cells from people with SCA7 and from healthy individuals. These cells were reprogrammed into induced pluripotent stem cells (iPSCs), which can develop into many different cell types. The stem cells were then converted into neurons and astrocytes, allowing the researchers to study how SCA7 affects human brain cells in the laboratory while preserving each patient’s unique genetic makeup.

As expected, the patient-derived cells carried an expanded number of CAG repeats (61–67) in the ATXN7 gene, confirming that the laboratory-grown cells accurately represented SCA7. When the researchers examined the neurons, they found that the overall number and appearance of the cells were similar to those of healthy individuals. However, the neurons developed fewer branches, which are important for forming connections with other nerve cells. Fewer branches suggest that communication between neurons may already be impaired, even before large numbers of cells are lost.

The researchers then turned their attention to astrocytes, where they made one of the study’s most important discoveries. Astrocytes from people with SCA7 showed lower levels of proteins that normally identify healthy astrocytes, suggesting that these support cells were not developing or functioning normally. This finding is important because astrocytes play a critical role in keeping neurons healthy. If astrocytes become impaired, they may be less able to provide the support that neurons need to survive.

To better understand what was happening inside these cells, the researchers examined which genes were turned on or off. They found widespread changes in 349 genes involved in brain development, communication between neurons, and energy metabolism. Several genes that normally help immature brain cells develop into healthy, mature neurons were less active, suggesting that important developmental pathways were disrupted in SCA7.

Another key finding was that many of the altered genes were involved in energy production. Healthy brain cells require large amounts of energy to function, and neurons are particularly dependent on astrocytes to help meet these energy demands. The researchers found evidence that cellular pathways involved in metabolism and the response to oxygen were disrupted in SCA7 cells. They also observed changes in proteins involved in communication between neurons, indicating that both neuronal signaling and cellular metabolism were affected.

To determine whether these genetic changes affected cell function, the researchers measured how efficiently the cells produced energy. They found that neurons derived from people with SCA7 consumed less oxygen, produced less ATP, the cell’s main energy source, and had a reduced capacity to generate energy when needed. These findings suggest that SCA7 neurons may struggle to meet the high energy demands required for normal brain function. Because astrocytes normally provide metabolic support to neurons, the loss of healthy astrocytes could further worsen this energy shortage, making neurons even more vulnerable to damage over time.

Although this study does not provide immediate treatment for SCA7, it offers important new insights into how the disorder develops. Previous research has focused primarily on neurons, but these findings suggest that astrocytes may also play a significant role in disease progression. By demonstrating that both neurons and their supporting cells are dysfunctional, the study broadens our understanding of SCA7 and highlights astrocytes as a potential target for future research. In addition, the patient-derived cell model developed in this study closely reflects the genetics of people living with SCA7, making it a valuable tool for studying disease mechanisms and testing future therapies. Together, these findings remind us that understanding all the cells involved, not just neurons, may be essential for developing effective treatments for SCA7.