Health (Commonwealth Union) – Spinocerebellar ataxia 4 (SCA4), a progressive neurological ailment, though rare, exerts severe impacts on patients and their families. Typically, its initial manifestation is evident through difficulties in walking and balancing, exacerbating over time. Onset commonly arises in one’s forties or fifties, yet in some cases, it can emerge as early as the late teens. Unfortunately, there exists no known cure, and until recently, the etiology remained elusive.
After enduring 25 years of uncertainty, a collaborative international effort, spearheaded by Dr. Stefan Pulst and K. Pattie Figueroa, both affiliated with the Spencer Fox Eccles School of Medicine at the University of Utah, has definitively unraveled the genetic underpinnings of SCA4. Their groundbreaking findings, detailed in the journal Nature Genetics, provide long-awaited answers to affected families and pave the way for prospective treatments.
SCA4’s hereditary pattern has long suggested a genetic origin, with prior investigations localizing the responsible gene to a specific chromosomal region. However, this region posed formidable challenges for analysis, characterized by repetitive segments resembling fragments of other chromosomes and possessing an atypical chemical composition, impeding most genetic testing methodologies.
To elucidate the causal mutation underlying SCA4, Figueroa, Pulst, and their collaborative team harnessed cutting-edge sequencing technologies. Through comparative analysis of DNA samples from affected and unaffected individuals across multiple Utah families, they identified a notable anomaly within a gene known as ZFHX3 in SCA4 patients. Specifically, a segment within ZFHX3 exhibited excessive length, harboring an elongated string of repetitive DNA sequences.
Subsequent experimentation with isolated human cells carrying the extended version of ZFHX3 revealed indications of cellular dysfunction. These cells exhibited impaired protein recycling capabilities and exhibited the presence of protein aggregates, suggesting compromised cellular health.
“This mutation is a toxic expanded repeat and we think that it actually jams up how a cell deals with unfolded or misfolded proteins,” explained Pulst, who is the final author on the study. Healthy cells require continuous degradation of non-functional proteins. The researchers demonstrated that the mutation responsible for SCA4 disrupts the protein-recycling process in cells, potentially leading to toxicity in nerve cells.
Interestingly, a comparable phenomenon appears to occur in another type of ataxia, SCA2, which also disrupts protein recycling. Currently, researchers are conducting clinical trials for a potential therapy for SCA2. The parallels between these two conditions suggest that the treatment might also be beneficial for patients with SCA4.
The discovery of the genetic change that brings about SCA4 is vital to develop improved treatments, indicated Pulst who also said “The only step to really improve the life of patients with inherited disease is to find out what the primary cause is. We now can attack the effects of this mutation potentially at multiple levels.”
Although the development of treatments will likely be a prolonged process, understanding the underlying cause of the disease can be immensely valuable for families impacted by SCA4, according to Figueroa, the study’s lead author. Individuals within affected families can ascertain whether they carry the genetic mutation responsible for the disease, aiding in making informed life choices such as family planning.
“They can come and get tested and they can have an answer, for better or for worse,” said Figueroa.
The researchers underscore the indispensable role played by the generosity of SCA4 patients and their families in enabling their discoveries. Through the sharing of family records and biological samples, they were able to juxtapose the DNA of affected and unaffected individuals. Figueroa expresses gratitude, noting that various branches of these families not only opened their homes but also shared their histories. Family records were comprehensive enough to enable the tracing of the disease’s origins in Utah back to a pioneer couple who settled in Salt Lake Valley in the 1840s.
For Figueroa, studying SCA4 has evolved into a personal journey since encountering numerous families affected by the disease. She, has been directly involved in SCA4 research since 2010 when the first family reached out to him. Engaging with these families on a personal level has transformed them from mere numbers on DNA vials to individuals he interacts with daily. She further indicated that she cannot just walk away from that, as this is not merely science; it’s someone’s life.
The findings of this research appeared in Nature Genetics under the title “GGC expansion in ZFHX3 causes SCA4 and impairs autophagy.”
