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Human-specific protein drives dynamic DNA changes in neurodegenerative conditions
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Human-specific protein drives dynamic DNA changes in neurodegenerative conditions


SickKids researchers identified a protein which may be responsible for the progression of genetic conditions and present a new therapeutic target.

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Researchers at The Hospital for Sick Children (SickKids) have identified that a human-specific protein may be driving the progression of inherited health conditions.

Human genes are enriched with tracts of repeated DNA sequences. When these sequences occur one after the other, as if the same word is written over and over again, it is called a tandem repeat. Everyone has these repeat sequences in their genome but in some individuals these repeat tracts have expanded to be much longer than they should be. These expansions are a source of genetic variation which can be the cause of health conditions.  

In total, 70 different conditions are caused by expansions of tandemly repeated DNA tracts, including Huntington’s disease (HD) and Spinocerebellar Ataxia type 1 (SCA1) – two conditions associated with neurodegeneration that progresses with age. In HD and SCA1, the inherited repeat expansion is dynamic and ever-changing, such that the length of the expanded repeat gets larger within a person’s brain as they age. Since these ongoing DNA expansions are associated with more severe illness, understanding why these repeats get larger over time is critically important. 

Published in Cell, the study examined the roles of two proteins that prevent or encourage repeat expansions with age: RPA and Alternative-RPA (Alt-RPA), respectively. Though RPA is found in all life and helps to stabilize and prevent these genetic variations, the role of Alt-RPA, which is specific to humans, has been relatively unknown until now.

The biology of DNA is very important and is imperative to maintain the stability of a human genome,” explains Dr. Christopher Pearson, Senior Scientist in the Genetics & Genome Biology program and senior author on the study. “The human-specific Alt-RPA has been under-studied until now, but it may explain why humans and not other animals are susceptible to certain genetic conditions and presents a new therapeutic target to investigate.”

Exposing the role of Alt-RPA   

Normally, DNA is composed of two strands that are paired to each other like a zipped-up zipper. When DNA becomes un-zipped and single stranded, unusual structures can form within the repeated DNAs. These unusual structures can lead to more repeat expansions over time.  

By studying the function of the two protein forms, the international team of specialists uncovered that Alt-RPA encourages these unusual structures within tandemly repeated DNA, while RPA prevents them from forming. What’s more, the researchers found much higher Alt-RPA levels in brains of people with DNA repeat conditions like HD and SCA1.  

 “Since Alt-RPA drives the ongoing repeat expansions that worsens the severity and progress of these conditions, blocking Alt-RPA specifically could inform future treatment,” explains Pearson.

Protein may inform future clinical interventions 

Going forward, the research team will continue to demystify the functions of Alt-RPA and identify ways to inhibit Alt-RPA while leaving canonical RPA unaffected. They are also interested in understanding the roles of RPA and Alt-RPA in other human conditions, including cancer.  

 “It’s important for biologists, and everyone who is studying DNA and RNA, to understand the role of Alt-RPA,” says Dr. Terence Gall-Duncan, first author on the paper and a post-doctoral fellow in the Pearson Lab.Although our research is focused on rare diseases, I hope people explore Alt-RPA as a potential driver of many health conditions.” 

The study emphasizes the importance of studying human-specific factors in health conditions which may be overlooked in animal models.  

Gall-Duncan adds, “We were fortunate to be able to study Huntington’s Disease and Spinocerebellar Ataxia Type 1 tissues that were generously donated to science. These brain tissues were essential for our discovery of the involvement of the human-specific Alt-RPA. We sincerely thank all of the families who donated tissues that were necessary for this study.”  

This research was funded by The Canadian Institutes of Health Research, the Hereditary Disease Foundation, the Natural Sciences and Engineering Research Council of Canada, Tribute Communities, Marigold Foundation, the Petroff Family Fund, Kazman Family Foundation and the Fox Family Fund. 

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