Pinpointing the cause of a neurodegenerative disorder ( rfered with normal clearance of Ataxin-...)

Pinpointing the cause of a neurodegenerative disorder

rfered with normal clearance of Ataxin-1, meaning that it accumulated in cells," said Zoghbi. She noted that earlier studies yielded hints that the glutamine repeats somehow caused Ataxin-1 function to be altered in a way that damaged or killed Purkinje cells.

"We had been accumulating clues that the glutamine tract expansion is clearly what is important for disease because that's the mutation," said Zoghbi. "But we also concluded that there was something else beyond the glutamine that's really mediating the toxicity of the protein." Those conclusions were based, in part, on experiments in mice that showed that increased levels of normal Ataxin-1 can cause the pathology of SCA1.

Turning to the fruit fly, Drosophila, a favorite of geneticists, Zoghbi and her colleagues showed that a particular domain of Ataxin-1 was responsible for causing the flies to lose sensory neurons, but the domain's function remained unknown. Then, a finding by co-author Hugo Bellen, an HHMI investigator at Baylor, set the researchers off in a more fruitful direction. Bellen's team was doing experiments designed to identify proteins that interact with the Drosophila protein, Senseless. His group discovered serendipitously that Senseless interacts with the Ataxin-1 domain and is important for nervous system development.

In further experiments in flies, Zoghbi and her colleagues showed that increases in Ataxin-1 reduced levels of Senseless during peripheral nervous system development, causing developmental abnormalities. Additional experiments demonstrated that enhanced levels of normal and abnormal human Ataxin-1 produced even more serious pathology in the flies.

The researchers then showed that the same interaction and pathological effects occurred in mice -- in which Ataxin-1 affected the mammalian version of Senseless, which is called GFi-1. And, they found that mice lacking GFi-1 showed Purkinje cell degeneration, just like humans with SCA1.

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Source:Howard Hughes Medical Institute

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