Pinpointing The Cause Of A Neurodegenerative Disorder

People who are afflicted with the rareneurodegenerative disorder spinocerebellar ataxia type 1 (SCA1) sufferdamage to cerebellar Purkinje cells caused by a toxic buildup of theprotein Ataxin-1. Researchers knew that SCA1, Huntington's disease andother related disorders arise because of a “genetic stutter,” in whicha mutation causes a particular gene sequence to repeat itself. Theseabnormal genetic repeats cause the resulting proteins to containunusually long repetitive stretches of the amino acid glutamine.

Thenew findings, which are published in the August 26, 2005, issue of thejournal Cell, provide a molecular explanation for Ataxin-1's assault oncerebellar Purkinje cells.

The findings should help to understanda range of diseases, including Huntington's disease, which are causedby an abnormal number of repetitive gene sequences. The discovery mayalso offer a new conceptual approach to understanding the pathology ofParkinson's disease and Alzheimer's disease, according to Huda Y.Zoghbi, a Howard Hughes Medical Institute investigator at the BaylorCollege of Medicine.

People with polyglutamine repeat disorderssuffer severe degeneration in particular groups of neurons that varydepending on the type of disease. In SCA1, for example, the buildup ofAtaxin-1 damages the cerebellar Purkinje cells. As a result of thedamage, people with SCA1 lose balance and motor coordination. Loss ofmuscle control worsens until patients can no longer eat or breathe.

“Wehad known that the expansion of the glutamine tract within Ataxin-1probably interfered with normal clearance of Ataxin-1, meaning that itaccumulated in cells,” said Zoghbi. She noted that earlier studiesyielded hints that the glutamine repeats somehow caused Ataxin-1function to be altered in a way that damaged or killed Purkinje cells.

“Wehad been accumulating clues that the glutamine tract expansion isclearly what is important for disease because that's the mutation,”said Zoghbi. “But we also concluded that there was something elsebeyond the glutamine that's really mediating the toxicity of theprotein.” Those conclusions were based, in part, on experiments in micethat showed that increased levels of normal Ataxin-1 can cause thepathology of SCA1.

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

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

Theresearchers then showed that the same interaction and pathologicaleffects occurred in mice — in which Ataxin-1 affected the mammalianversion of Senseless, which is called GFi-1. And, they found that micelacking GFi-1 showed Purkinje cell degeneration, just like humans withSCA1.

“The overall picture we have now is that glutamineexpansion causes some aspects of the pathology of SCA1 in part byenhancing the activity of the domain that is outside the glutaminerepeat,” said Zoghbi.

The finding offers insight into themolecular mechanisms that cause SCA1, Huntington's disease and otherglutamine repeat disorders, said Zoghbi. “It seems to be a recurringtheme in neurodegenerative disorders that having extra copies of anormal protein, not just a mutated one, can cause pathology. There havebeen observations that having extra copies of the normal alphasynuclein protein that causes Parkinson's disease, or of the amyloidprecursor protein that causes Alzheimer's disease, can causepathology,” she said. “So, this raises the question of whethermutations in the genes for these proteins enhance their normal action.

“Importantly,such insights can now guide studies that focus on the normal functionand interactions of these proteins and how they might be enhanced bydisease-causing mutations," said Zoghbi. "These studies could givebetter understanding of how the proteins cause disease.”