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Environmental Factor

Environmental Factor

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August 2018

Mechanism behind rare ataxia disease found by NIEHS scientists

People born with a rare disorder known as ataxia with oculomotor apraxia 1 (AOA1) have problems coordinating body movements and difficulty walking. They are also unable to move their eyes side-to-side and must use their peripheral vision to see by turning their head. No specific treatment exists for this debilitating condition, but NIEHS researchers have now reported the mechanism behind it.

Scott Williams Williams is deputy chief of the NIEHS Genome Integrity and Structural Biology Laboratory and head of the Structural Cell Biology Group. (Photo courtesy of Steve McCaw)

The results, published June 22 in the European Molecular Biology Organization (EMBO) Journal, are a continuation of their aprataxin research that appeared in the journal Nature (see sidebar).

A team led by NIEHS researcher Scott Williams, Ph.D., and NIEHS fellow Percy Tumbale, Ph.D., have shown how the protein aprataxin recognizes DNA damage, or lesions, and how in those with AOA1, aprataxin is inactivated.

Using biochemical and structural studies, they found that in AOA1, aprataxin mutations affect protein stability, how repair proteins bind to DNA, and the rate of the chemical reaction, which is known as catalysis. The team also uncovered a dominant mutation that affects the enzymatic reaction that normally reverses DNA damage.

"If aprataxin is inactive and not doing its job, it will impact DNA repair function in cells and cause AOA1," Tumbale said. "Our characterization of AOA1 mutants may help explain why there is a range of symptoms in these patients, from early onset through late onset."

Wedging to repair damage

Williams said when aprataxin is working properly, it uses a wedge-pivot-cut process to recognize DNA damage and create a kink in the DNA. Like a woodworker that uses a triangle wedge to pry open a piece of wood, aprataxin wedges into the DNA damage, kinks it 90 degrees, then cuts out the lesion.

"The DNA damage involves bulky lesions that develop on the ends of DNA," Williams said. "The wedging mechanism allows aprataxin to expose damaged DNA ends and make it possible for other DNA repair proteins to gain access to these ends."

Percy Tumbale Tumbale is an Intramural Research Training Award (IRTA) fellow in the Williams group. (Photo courtesy of Steve McCaw)

Living with AOA1

When aprataxin does not work properly, it gives rise to AOA1, a rare disorder that affects 1 in 100,000 people. Williams and Tumbale said that as people with AOA1 age, they will experience a degeneration of the area of the brain know as the cerebellum, which is characteristic of a lot of DNA repair disorders.

The researchers do not understand exactly how this brain deterioration happens, but over time — generally by adolescence — AOA1 patients are wheelchair bound.

Tumbale received a research grant from the National Ataxia Foundation a few years ago and was fortunate to travel to some of the organization’s meetings. She said meeting AOA1 patients and their families changed her perspective from just doing experiments at the bench. She realized what she was working on could lead to positive changes in their lives.

"They really appreciated that someone was out there trying to understand their disease, and it motivated me to work harder," Tumbale said. "Hopefully, these findings will lead to a treatment to help them one day."

Citation: Tumbale P, Schellenberg MJ, Mueller GA, Fairweather E, Watson M, Little JN, Krahn J, Waddell I, London RE, Williams RS. 2018. Mechanism of APTX nicked DNA sensing and pleiotrophic inactivation in neurodegenerative disease. EMBO J 37(14):e98875.


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